TW201924663A - Transdermal therapeutic system comprising polyoxyxacrylic hybrid polymer for transdermal administration of guanfacine - Google Patents

Abstract

The invention relates to a transdermal therapeutic system for percutaneous administration of guanfacine, which includes a layer structure containing guanfacine, the layer structure containing guanfacine comprises:
A) Backing layer; and
B) The layer containing guanfacine;
Wherein the transdermal therapeutic system includes at least one polysiloxane acrylic hybrid polymer.

Description

Transdermal therapeutic system containing polysiloxane-based acrylic hybrid polymer for transdermal administration of guanfacine

The present invention relates to a transdermal therapeutic system (TTS) for transdermal administration of guanfacine to systemic circulation, as well as a manufacturing method, therapeutic method, and use thereof.

Active agent guanfacine (also known as N- (aminoiminomethyl) -2,6-dichloro-phenethylamide, C ₉ H ₉ Cl ₂ N ₃ O, CAS No. 29110- 47-2) is a sympathetic blocker for the treatment of hypertension and attention deficit hyperactivity disorder (ADHD). It is a centrally acting α (2) -adrenergic receptor agonist. It has the following chemical formula:
.

Currently, guanfacine is commercially available, for example, in the form of immediate release or controlled release tablets containing from 1 to 4 mg guanfacine. Lozenges are suitable for administration once a day.

However, oral administration of active agents has disadvantages, for example in terms of patient compliance. In addition, once the extended-release tablets are ingested, it is not possible to quickly terminate the treatment, for example, in view of overdose or signs of intolerance.

Therefore, there is a need for a percutaneous treatment system for percutaneous administration of guanfacine. In particular, there is a need for TTS suitable for multi-day therapy with a single application to improve patient compliance.

The purpose and summary of the present invention

The object of the present invention is therefore to provide TTS for transdermal administration of guanfacine. In particular, the object of the present invention is to provide TTS for transdermal administration of guanfacine, which provides a skin penetration rate sufficient to achieve a therapeutically effective dose.

Another object of the present invention is to provide TTS for percutaneous administration of guanfacine to provide a therapeutically effective amount of guanfacine for at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours. In particular, the object of the present invention is to provide a therapeutically effective amount over the entire period of time, wherein TTS is applied to the skin by replacing after an application time of, for example, at least 24 hours, preferably at least 72 hours, more preferably about 84 hours TTS allows 24/7 treatment.

Another object of the present invention is to provide TTS for transdermal administration of guanfacine, wherein the fluctuation in plasma concentration of guanfacine is reduced when compared with oral administration, especially in a stable state.

Another object of the present invention is to provide TTS for transdermal administration of guanfacine, which has a high utilization rate of active ingredients.

Another object of the present invention is to provide a TTS for transdermal administration of guanfacine, which meets the requirements of convenient application and / or is easy to manufacture and cost-effective from the viewpoint of size and thickness.

These and other objects are achieved by the present invention. According to one aspect of the present invention, it relates to a transdermal therapeutic system for percutaneous administration of guanfacine, which includes a layer structure containing guanfacine, which contains guanfacine The layer structure includes:
A) Backing layer; and
B) A layer containing guanfacine;
Wherein the transdermal therapeutic system includes at least one polysiloxane acrylic hybrid polymer.

It has been found that the TTS according to the present invention comprising a polysiloxane-based acrylic hybrid polymer provides advantageous properties in terms of constant and continuous guanfacine delivery. In particular, the TTS according to the present invention provides an appropriate guanfacine permeability and an appropriate penetration amount over a period of at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours.

According to certain aspects, the invention also relates to a transdermal therapeutic system for transdermal administration of guanfacine as described above,
The guanfafaxin-containing layer is a guanfafaxin-containing matrix layer, which includes:
i) guanfacine; and
ii) At least one polysiloxane acrylic hybrid polymer.

In certain preferred embodiments, the guanfacine-containing layer structure further comprises at least one additive selected from the group consisting of dispersants, penetration enhancers, and co-solvents.

According to a specific aspect, the present invention relates to a transdermal therapeutic system for percutaneous administration of guanfacine, which includes a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising:
A) Backing layer; and
B) a layer containing guanfacine, preferably a matrix layer containing guanfacine, which contains;
i) Guanfacine, the amount of which is from 3 to 13% by weight based on the total weight of the layer containing guanfacine;
ii) at least one polysiloxane acrylic hybrid polymer in an amount of from 74 to 89% by weight based on the total weight of the guanfacine-containing layer;
iii) at least one dispersant, the amount of which is from 2 to 6% by weight based on the total weight of the guanfacine-containing layer;
iv) at least one penetration enhancer in an amount of from 2 to 6% by weight based on the total weight of the guanfacine-containing layer; and
v) Optionally at least one co-solvent in an amount of from 0.5 to 4% by weight based on the total weight of the guanfacine-containing layer.

According to some embodiments of the present invention, the transdermal therapeutic system according to the present invention is used in a method of treating a human patient, preferably a method of treating a human patient from 6 to 17 years old. In particular, the transdermal therapeutic system according to the present invention is used to treat high blood pressure or attention deficit hyperactivity disorder (ADHD) in human patients (preferably human patients aged 6 to 17 years) and / or as a stimulus In the method of adjuvant therapy of drug therapy. For these medical uses, the TTS according to the present invention is preferably applied to the patient's skin for at least 24 hours, more preferably at least 72 hours, and most preferably about 84 hours.

According to some embodiments, the present invention further relates to a method of treating human patients (preferably human patients aged from 6 to 17 years) by applying the transdermal therapeutic system according to the present invention to the skin of patients . In particular, the present invention relates to a method for treating hypertension or attention deficit hyperactivity disorder (ADHD) in human patients (preferably human patients aged from 6 to 17 years) by applying the experience according to the present invention The skin treatment system is applied to the patient's skin. Regarding these methods, it is preferred that the TTS system according to the present invention is applied to the patient's skin for at least 24 hours, more preferably at least 72 hours, and most preferably about 84 hours.

According to another aspect, the present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine, which includes a layer structure containing guanfacine, wherein the transdermal therapeutic system provides one or more by transdermal delivery A pharmacokinetic parameter selected from the group consisting of:
AUC _0-24 from 10 to 600 (ng / mL) h,
AUC _0-72 from 30 to 1800 (ng / mL) h,
AUC _0-84 from 35 to 2100 (ng / mL) h,
The ratio of C _max to C ₂₄ less than 2.0,
The ratio of C _max to C ₇₂ less than 3.0, and the ratio of C _max to C ₈₄ less than 3.5.

According to yet another aspect, the present invention relates to a transdermal therapeutic system containing guanfacine, which is used for the transdermal administration of guanfacine to treat human patients (preferably human patients aged from 6 to 17 years) In the method, wherein the transdermal therapeutic system is applied to the patient's skin for at least 24 hours, preferably at least 72 hours, more preferably about 84 hours.

According to yet another aspect, the present invention relates to guanfacine, which is used in a method of percutaneous administration of guanfacine with a transdermal therapeutic system to treat human patients (preferably human patients from 6 to 17 years old) , Wherein the transdermal therapeutic system is applied to the patient's skin for at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours.

According to yet another aspect, the present invention relates to a method of transdermal administration of guanfacine to treat human patients (preferably human patients from 6 to 17 years old), wherein the transdermal therapeutic system is applied to the patient The skin experiences at least 24 hours, preferably at least 72 hours, more preferably about 84 hours.

According to another aspect, the invention relates to a method of manufacturing a guanfacine-containing layer for use in a transdermal therapeutic system according to the invention, which comprises the following steps:
1) Combine at least the following components
i) guanfacine; and
ii) at least one polysiloxane acrylic hybrid polymer;
To obtain a coating composition;
2) Coat the coating composition on the backing layer or release liner to obtain the coated coating composition; and
3) The coated coating composition is dried to form a guanfacine-containing layer.

Preferably, the polysiloxane-acrylic hybrid polymer is provided as a solution, wherein the solvent is ethyl acetate or n-heptane, preferably ethyl acetate.

According to yet another aspect, the invention relates to a percutaneous treatment system obtainable by the method according to the invention.

definition

Within the meaning of the present invention, the term "transdermal therapeutic system" (TTS) refers to a system in which an active agent (eg guanfacine) is administered to the systemic circulation via transdermal delivery and refers to the entire individual drug delivery unit, which The patient's skin and the therapeutically effective amount of the active agent contained in the active agent-containing layer structure and the optional additional adhesive cover layer on top of the active agent-containing layer structure are applied after removing the optionally existing release liner. The active agent-containing layer structure may be located on the release liner (detachable protective layer), and therefore, the TTS may additionally include the release liner. Within the meaning of the present invention, the term "TTS" particularly refers to a system that provides transdermal delivery, for example, via iontophoresis or microperforation, excluding active delivery. Transdermal therapeutic systems can also be referred to as transdermal drug delivery systems (TDDS) or transdermal delivery systems (TDS).

Within the meaning of the present invention, the term "guanfacine-containing layer structure" refers to a layer structure containing a therapeutically effective amount of guanfacine and comprising a backing layer and at least one guanfacine-containing layer. Preferably, the layer structure containing guanfacine is a self-adhesive layer structure containing guanfacine.

Within the meaning of the present invention, the term "therapeutically effective amount" means that when TTS is administered to a patient, the amount of active agent in the TTS is sufficient to treat, prevent or reduce hypertension or attention deficit hyperactivity disorder in human patients (ADHD) or adjuvant therapy sufficient to stimulate drug therapy in human patients. TTS usually contains more actives in the system than is actually provided to the skin and systemic circulation. This excess of active agent is usually necessary to provide sufficient driving force for delivery from TTS to the systemic circulation.

Within the meaning of the present invention, the terms "active", "active agent" and the like, and the term "guanfacine" refer to guanfacine in any pharmaceutically acceptable chemical and morphological form and physical state. These forms include but are not limited to guanfacine in its free base form, protonated or partially protonated guanfacine, guanfacine salt, and especially acid addition salts formed by the addition of inorganic or organic acids, such as Guanfacine hydrochloride or guanfacine tartarate, solvates, hydrates, cage compounds, co-crystals, composites, etc., as well as the guanidine method in the form of micronizable, crystalline and / or amorphous particles Xin, and any mixture of the foregoing forms. Guanfacine is preferably present in dispersed form when contained in a medium such as a solvent.

When referring to the use of guanfacine in a specific form for the manufacture of TTS, this does not exclude the interaction between this form of guanfacine and other components of the guanfacine-containing layer structure in the final TTS, such as salt formation Or compound effect. This means that even if the included guanfacine system is in its free base form, it can be present in the final TTS in protonated or partially protonated form or as an acid addition salt, or if the included guanfacine system is in the form of In salt form, a part of it can still be present in the final TTS as free base. Unless otherwise indicated, the amount of guanfacine in the layer structure is specifically related to the amount of guanfacine included in the TTS during the manufacture of TTS, and is calculated on the basis of guanfacine in the form of a free base. For example, when a) 0.1 mmol (equal to 24.61 mg) guanfacine base or b) 0.1 mmol (equal to 27.71 mg) guanfacine hydrochloride is included in the TTS during manufacturing, then within the meaning of the present invention, in the layer The amount of guanfacine in the structure is 24.06 mg in both cases, which is 0.1 mmol.

The guanfacine starting material included in the TTS during TTS manufacturing may be in the form of particles. Guanfacine can be present in the active agent-containing layer structure in the form of particles, for example, and the particles are preferably uniformly dispersed within the active agent-containing layer structure.

Within the meaning of the present invention, the term "particle" refers to a solid particulate material containing individual particles, the size of which is insignificant compared to the material. In particular, the particles are solids including amorphous and crystalline materials, including plastic / deformable solids.

Within the meaning of the present invention, the term "dispersed" refers to a step or combination of steps in which the starting material (eg guanfacine) is made insoluble or incompletely dissolved. In the sense of the present invention, dispersion comprises dissolving a part of the starting material (eg guanfacine particles), which depends on the solubility of the starting material (eg guanfacine in the coating composition).

There are two main types of TTS used for active agent delivery, namely matrix TTS and reservoir TTS. The release of the active agent in the matrix TTS is mainly controlled by the matrix including the active agent itself. In contrast, depot TTS typically requires a rate control membrane that can control the release of active agent. In principle, the matrix TTS can also contain a rate-controlling membrane. However, compared to the reservoir-type TTS, the matrix-type TTS has the advantage that a rate-determining membrane is generally not required, and dose dumping does not occur due to membrane rupture. In summary, the stromal-type transdermal therapeutic system (TTS) is less complicated to manufacture and the patient can use it easily and conveniently.

Within the meaning of the present invention, "matrix TTS" refers to a system or structure in which the active substance is uniformly dissolved and / or dispersed in a polymer carrier (ie, matrix), the polymer carrier and the active agent and optionally the rest The matrix layer is formed. In this system, the matrix layer controls the release of active agent from the TTS. Preferably, the matrix layer has sufficient self-supporting adhesion, so there is no need to seal between other layers. According to this, in one embodiment of the present invention, the active agent-containing layer may be an active agent-containing matrix layer, wherein the active agent is uniformly distributed in the polymer matrix. In some embodiments, the active agent-containing matrix layer may include two active agent-containing matrix layers, and the two may be laminated together. The matrix-type TTS may be particularly in the form of a "drug-in-adhesive" type TTS, which refers to a system in which the active substance is uniformly dissolved and / or dispersed in a pressure-sensitive adhesive matrix. In this regard, the active agent-containing matrix layer may also be referred to as an active agent-containing pressure-sensitive adhesive layer or an active agent-containing pressure-sensitive adhesive matrix layer. TTS containing active agents dissolved and / or dispersed in a polymer gel (eg, hydrogel) is also considered a matrix type according to the present invention.

TTS with a reservoir containing liquid active agent is also referred to by the term "reservoir-type TTS". In this system, the release of the active agent is preferably controlled by the rate control membrane. In particular, the reservoir is sealed between the backing layer and the rate control membrane. Accordingly, in one embodiment, the active agent-containing layer may be an active agent-containing reservoir layer, which preferably contains a liquid reservoir, the reservoir containing the active agent. In addition, the reservoir type TTS usually additionally includes a skin contact layer, wherein the reservoir layer and the skin contact layer can be separated by a rate control film. In the reservoir layer, the active agent is preferably dissolved in a solvent (such as ethanol or water) or silicone oil. The skin contact layer usually has adhesive properties.

Within the meaning of the present invention, a reservoir type TTS is not understood as a matrix type. However, micro-reservoir-type TTS (a two-phase system in which deposits (eg, spheres, droplets) with active-containing phases dispersed in the outer polymer phase) are considered as matrix-type TTS and reservoirs in this technology The hybrid form of the TTS type differs from the uniform single-phase matrix type TTS and the reservoir type TTS in the concept of drug delivery and drug delivery. The micro-reservoir type TTS is considered to be a matrix type within the meaning of the present invention. The size of the micro-reservoir droplets can be determined by optical microscopy (eg Leica MZ16 including a camera (eg Leica DSC320)), which is achieved by a magnification between 10 and 400 times (depending on (Depending on the required detection limit) Take pictures of the micro-reservoir at different locations. By using imaging analysis software, the size of the microreservoir can be determined.

Within the meaning of the present invention, the term "active agent-containing layer" refers to a layer containing an active agent and providing a release area. The term covers the active agent-containing matrix layer and the active agent-containing reservoir layer. If the active agent-containing layer is an active agent-containing matrix layer, the layer is present in the matrix-type TTS. If the polymer is a pressure-sensitive adhesive, the matrix layer can also be expressed as the adhesive layer of TTS, so no additional skin contact layer is present. Alternatively, an additional skin contact layer may be present as an adhesive layer and / or provide an adhesive cover layer. Usually an additional skin contact layer is made so that it is free of active agent. However, due to the concentration gradient, the active agent migrates from the matrix layer to the additional skin contact layer over time until equilibrium is reached. The additional skin contact layer may be present on the active agent-containing matrix layer or separated from the active agent-containing matrix layer by a film (preferably a rate control film). Preferably, the active agent-containing matrix layer has sufficient adhesive properties, so no additional skin contact layer is present. If the active agent-containing layer is an active agent-containing reservoir layer, the layer exists in the reservoir-type TTS, and the layer contains the active agent in the liquid reservoir. In addition, there is preferably an additional skin contact layer in order to provide adhesive properties. Preferably, the rate control membrane separates the reservoir layer from the additional skin contact layer. An additional skin contact layer can be made so that it contains no active agent or contains active agent. If the additional skin contact layer contains no active agent, the active agent will migrate from the reservoir layer to the skin contact layer over time due to the concentration gradient until equilibrium is reached. In addition, an adhesive cover can be provided.

As used herein, the active agent-containing layer is preferably an active agent-containing matrix layer, and it is referred to as the final set layer. Preferably, the active agent-containing matrix layer is obtained after coating and drying the solvent-containing coating composition as described herein. Or the matrix layer containing the active agent is obtained after melt coating and cooling. The active agent-containing matrix layer can also be manufactured by laminating two or more such solidified layers (for example, dried or cooled layers) having the same composition to provide a desired area weight. The matrix layer can be self-adhesive (in the form of a pressure-sensitive adhesive matrix layer), or the TTS can contain an additional skin-contacting layer of pressure-sensitive adhesive to provide sufficient adhesion. Preferably, the matrix layer is a pressure-sensitive adhesive matrix layer. Optionally, the adhesive cover layer can be present at will.

Within the meaning of the present invention, the term "pressure-sensitive adhesive" (also abbreviated as "PSA") refers to adhesion with finger pressure in particular, permanent adhesion, exerting a strong holding force and should be removable from a smooth surface. Material that leaves no residue. When in contact with the skin, the pressure-sensitive adhesive layer is "self-adhesive", that is, it provides adhesion to the skin, so it generally does not require other auxiliary agents for fixing to the skin. The "self-adhesive" layer structure includes a pressure-sensitive adhesive layer for skin contact, which can be provided in the form of a pressure-sensitive adhesive matrix layer or in the form of an additional layer (ie, a pressure-sensitive adhesive skin contact layer). An adhesive cover layer can still be used to improve adhesion. The pressure-sensitive adhesive properties of the pressure-sensitive adhesive depend on the polymer or polymer composition used.

Within the meaning of the present invention, the term "polysiloxane-acrylic hybrid polymer" refers to a polymerization product that includes repeating units of the polysiloxane subclass and the acrylate subclass. The polysiloxane-acrylic hybrid polymer therefore contains a polysiloxane phase and an acrylic phase. Preferably, the polysiloxane-acrylic hybrid polymer contains a certain weight ratio (for example, from 60:40 to 40:60) of the polysiloxane phase and the acrylate phase, that is, the polysiloxane subclass and the acrylate subclass. The term "polysiloxane-acrylic blend" is intended to mean more than just a simple blend of polysiloxane-based and acrylate-based subclasses. Rather, the term indicates a polymerized hybrid species including polysiloxane-based subgroups and acrylate-based subclasses that have been polymerized together. The polysiloxyacrylic hybrid polymer may also be referred to as "polysiloxyacrylate hybrid polymer" because the terms acrylate and acrylic are used interchangeably in the context of the hybrid polymer used in the present invention.

Within the meaning of the present invention, the term "polysiloxane-acrylic hybrid pressure-sensitive adhesive" refers to a polysiloxane-acrylic hybrid polymer in the form of a pressure-sensitive adhesive. Polysiloxyacrylic hybrid pressure-sensitive adhesives are described in, for example, EP 2 599 847 and WO 2016/130408. Examples of polysiloxane-acrylic hybrid pressure-sensitive adhesives include PSA series 7-6100 and 7-6300 (7-610X and 7-630X; X = manufactured by Dow Corning and supplied in n-heptane or ethyl acetate) 1 based on n-heptane / X = 2 based on ethyl acetate). It has been found that, depending on the supply of polysiloxane-acrylic acid mixed with PSA solvent, the arrangement of polysiloxane and acrylic phases that form a continuous external phase of polysiloxane or acrylic acid and a corresponding discontinuous internal phase are different. If the polysiloxane-acrylic acid mixed PSA system is supplied in n-heptane, the composition contains a continuous polysiloxane outer phase and a discontinuous acrylic inner phase. If the polysiloxane-acrylic-based PSA composition is supplied in ethyl acetate, the composition contains a continuous acrylic external phase and a discontinuous polysiloxane internal phase.

Within the meaning of the present invention, the term "non-hybrid polymer" is used synonymously to exclude polymers of hybrid type. Preferably, the non-hybrid polymer is a pressure-sensitive adhesive (for example, a silicone-based or acrylate-based pressure-sensitive adhesive).

Within the meaning of the present invention, the term "silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality" includes silicone resins, silicone polymers, and Condensation reaction product of a silicon-based end-capping agent based on acrylate functionality. It should be understood that a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality may include only acrylate functionality, only methacrylate functionality, or acrylate functionality and methyl Both acrylate functionality.

As used herein, an active agent-containing matrix layer is a layer containing an active agent dissolved or dispersed in at least one polymer, or a layer containing an active agent dissolved in a solvent to form an active agent-solvent mixture, the activity The agent-solvent mixture is dispersed in the at least one polymer in the form of a precipitate (particularly droplets). Preferably, the at least one polymer is a polymer-based pressure-sensitive adhesive (for example, a polysiloxane-acrylic mixed pressure-sensitive adhesive). Within the meaning of the present invention, the term "pressure-sensitive adhesive layer" refers to a pressure-sensitive adhesive layer obtained from a solvent-containing adhesive coating composition after being coated on a film and evaporating the solvent.

Within the meaning of the present invention, the term "skin contact layer" refers to a layer included in the active agent-containing layer structure that directly contacts the patient's skin during administration. This may be an active agent-containing layer. When the TTS includes an additional skin-contacting layer, the other layers of the active agent-containing layer structure are not in contact with the skin and need not have self-adhesive properties. As outlined above, the additional skin contact layer adhered to the active agent-containing layer can absorb part of the active agent over time. An additional skin contact layer can be used to enhance adhesion. The size of the additional skin contact layer and the active agent-containing layer usually co-extend and correspond to the area of release. However, the area of the additional skin contact layer may also be larger than the area of the active agent-containing layer. In this case, the release area again refers to the area of the active agent-containing layer.

Within the meaning of the present invention, the term "area weight" refers to the dry weight of a specific layer (eg matrix layer) expressed in g / m ² . The area weight value accepts a tolerance of ± 10% due to manufacturing variability, preferably ± 7.5%.

If there is no other indication, "%" means% by weight (% by weight).

Within the meaning of the present invention, the term "polymer" refers to any substance composed of so-called repeating units obtained by polymerizing one or more monomers, and includes homopolymers composed of one type of monomers and Copolymer composed of two or more types of monomers. In the case of copolymers, the polymer can have any configuration of any arrangement of monomers, such as linear polymers, star polymers, comb polymers, brush polymers, such as alternating, statistical, block copolymers, or Branch polymer. The minimum molecular weight varies depending on the type of polymer and is known to the skilled person. The polymer may, for example, have a molecular weight greater than 2000, preferably greater than 5000 and more preferably greater than 10,000 Daltons. Compounds with a molecular weight of less than 2000, preferably less than 5000 or more preferably less than 10,000 Daltons are generally correspondingly called oligomers.

Within the meaning of the present invention, the term "crosslinking agent" refers to a substance capable of crosslinking the functional groups contained in the polymer.

Within the meaning of the present invention, the term "adhesive cover layer" refers to a self-adhesive layer structure that contains no active agent and has a larger area than the active agent-containing structure, and provides an additional area of adhesion to the skin but no active agent release area. This enhances the overall adhesive properties of TTS. The adhesive cover layer includes a backing layer and an adhesive layer that can provide closed or non-closed properties. Preferably, the backing layer to which the cover layer is bonded provides non-closed properties.

Within the meaning of the present invention, the term "backing layer" refers to the layer that supports the active agent-containing layer or the backing forming the adhesive cover layer. According to regulatory requirements, at least one backing layer in the TTS and the backing layer of the active agent-containing layer are substantially impermeable to the active agent contained in the layer during storage and administration, and thus prevent loss of activity or cross-contamination. Preferably, the backing layer is closed, which means substantially impermeable to water and water vapor. Suitable materials for the backing layer include polyethylene terephthalate (PET), polyethylene (PE), ethylene vinyl acetate-copolymer (EVA), polyurethane and mixtures thereof. Suitable backing layers are therefore, for example, PET laminates, EVA-PET laminates and PE-PET laminates. In a preferred embodiment, the backing layer is siliconized PET foil. Fabric or non-woven backing materials are also suitable.

The TTS according to the invention can be characterized by certain parameters measured by an in vitro skin penetration test.

Generally, in vitro penetration testing is performed in a Franz diffusion cell, using EVA membranes (such as 9% vinyl acetate and 50 µm thickness, preferably provided by 3M) and using phosphate buffer pH 5.5 or 7.4 as the acceptor medium ( 32 ° C, saline solution containing 0.1% sodium azide).

Furthermore, the in vitro penetration test can be performed in a Franz diffusion tank, using human or animal skin, preferably human skin with dermatomed split-thickness and intact epidermis with a thickness of 800 µm, and using phosphate Buffer pH 5.5 or 7.4 as the acceptor medium (32 ° C, saline solution containing 0.1% sodium azide), with or without the addition of up to 40% by volume of organic solvents (eg ethanol, acetonitrile, isopropanol, dipropylene glycol, PEG 400), such that the acceptor medium may contain, for example, 60 volume% phosphate buffer pH 5.5, 30 volume% dipropylene glycol and 10 volume% acetonitrile.

Without additional instructions, the in vitro penetration test system uses dermatomed split-thickness with 800 µm thickness and human skin with intact epidermis and phosphate buffer pH 5.5 as the receptor medium (32 ° C, Saline solution containing 0.1% sodium azide). The amount of active that penetrates into the receptor medium is determined using a validated HPLC method with a UV photometric detector to take sample volumes at regular intervals. When the sample volume is obtained, the receptor medium is completely or partially replaced with fresh medium, and the measured penetration of the active substance is related to the penetration between the two last sampling points, not the total penetration to the sampling point Quantity.

Therefore, in the meaning of the present invention, the parameter "penetration amount" is expressed in µg / cm ² and is related to the penetration amount of the active substance at a certain elapsed time point within the sample interval. For example, in the in vitro penetration test as described above, where the amount of active substance that has penetrated into the receptor medium has been measured, for example, at the 0, 2, 4, 8, 12, and 24 hours, it can be given, for example, from the 8th The "penetration" of the active substance at the sample interval from hour to 12 hours corresponds to the measurement at 12 hours, in which the receptor medium has been completely replaced at 8 hours.

The penetration amount can also be given as "cumulative penetration amount", which corresponds to the cumulative amount of permeated active substance at a certain time point. For example, in the in vitro penetration test as described above, the amount of the active substance that has penetrated into the receptor medium has been measured, for example, at the 0, 2, 4, 8, 12, and 24 hours, and the active substance at the 12th hour The "cumulative penetration amount" corresponds to the sum of the penetration amounts from the 0th hour to the 2nd hour, the 2nd hour to the 4th hour, the 4th hour to the 8th hour, and the 8th hour to the 12th hour.

Within the meaning of the present invention, the parameter "skin permeability" at a certain elapsed time within a certain sample interval is expressed in µg / (cm ² * h) and is measured from the in vitro penetration test as described above The permeation (µg / cm ² ) within the sample interval is calculated by dividing the number of hours between the sample intervals. For example, the skin penetration rate in the in vitro penetration test as described above (where, for example, the amount of active substance that has penetrated into the receptor medium has been measured at 0, 2, 4, 8, 12, and 24 hours), at the 12th The "skin permeability" of the hour is calculated by dividing the amount of penetration in the sample interval from the 8th hour to the 12th hour by 4 hours.

The "cumulative skin penetration rate" can be calculated from the respective cumulative penetration amount divided by the cumulative penetration amount over time. For example, in the in vitro penetration test as described above (where, for example, the amount of active that has penetrated into the receptor medium has been measured at 0, 2, 4, 8, 12, and 24 hours), the "accumulation at the 12th hour "Skin permeability" is calculated by dividing the cumulative penetration at 12 hours (see above) by 12 hours.

Within the meaning of the present invention, the above parameters "penetration" and "skin penetration" (and "cumulative penetration" and "cumulative skin penetration") refer to the average value calculated from at least 3 in vitro penetration test experiments . In the absence of other instructions, the standard deviation (SD) of these averages refers to the standard deviation of the calibrated sample calculated using the following formula:

Where n is the sample size, Is the observed value and It is the average of the observed values.

The TTS according to the invention can also be characterized by certain parameters as measured in in vivo clinical studies.

Within the meaning of the present invention, the parameter "average release rate" refers to the average release rate expressed in µg / h (µg / hour, µg / hr) or in mg / day during the administration period (eg 1 to 7 days) The active agent is thereby released into the systemic circulation through human skin, and is based on the AUC obtained during the administration period in clinical studies.

Within the meaning of the present invention, the term "extended period" refers to at least or about 24 hours, at least or about 48 hours, at least or about 72 hours, at least or about 84 hours, at least or about 1 day, at least or about 2 days, Or a period of at least or about 3 days, or at least or about 3.5 days, or about a period of about 24 hours to about 168 hours or 1 to 7 days, or about 24 hours to about 84 hours or 1 to 3.5 days.

For continuous drug therapy, the frequency of drug administration is preferably maintained at a frequency high enough to maintain the effective plasma concentration of the therapy. In other words, the interval between administration of the two dosage forms (also known as the administration interval) needs to be adjusted accordingly. Within the meaning of the present invention, the term "dosing interval" refers to the period between two consecutive TTS administrations, that is, the interval between the time points when two consecutive TTSs are applied to the patient's skin. Once applied, the TTS is usually maintained on the patient's skin for the entire dosing interval and is only removed at the end of the dosing interval, at which time a new TTS is applied to the skin. For example, if the dosing interval is 24 hours or 1 day, TTS is applied to and maintained on the patient's skin for 24 hours or 1 day. After 24 hours or 1 day, the TTS was removed from the skin and a new TTS was applied. Therefore, a 24-hour or 1-day dosing interval allows daily TTS replacement patterns during all-weather treatment. According to the invention, administration intervals of at least 72 hours, preferably about 84 hours, are preferred. It should be understood that the application time of TTS to the patient's skin is preferably the same as the time between dosing, which means that constant guanfacine administration is performed by changing TTS.

Within the meaning of the present invention, the term "room temperature" refers to the unregulated temperature in the laboratory room where the experiment is conducted and generally falls within 15 to 35 ° C, preferably within about 18 to 25 ° C.

Within the meaning of the present invention, the term "patient" refers to a subject who has presented a clinical manifestation of a particular symptom or symptom, etc., which is suggested to require treatment, a subject who undergoes preventatively or prophylactically treatment of the condition, or Subjects diagnosed with the condition to be treated. Preferably, the patient is 6 to 17 years old.

Within the meaning of the present invention, the term "pharmacokinetic parameters" refers to parameters that describe the plasma curves obtained in clinical studies (eg C _max , C _t and AUC _t1-t2 ), for example by using TTS containing active agents (Eg, guanfacine-containing TTS) is administered to healthy human subjects in a single dose, multiple doses, or steady state. Individual subjects' pharmacokinetic parameters are calculated using arithmetic and geometric mean values (such as average C _max , average AUC _t and average AUC _INF ) and additional statistical data (such as their respective standard deviations and standard errors, minimum and maximum values) And the median value (median) when the value list is ranked). In the context of the present invention, if there is no additional indication, the pharmacokinetic parameters (eg C _max , C _t and AUC _t1-t2 ) refer to the geometric mean. It cannot be ruled out that the absolute average value obtained with a certain TTS in clinical studies varies from study to study to some extent. In order to be able to compare the absolute average values between studies, reference formulations (such as any future product based on the invention) can be used as internal standards. AUC comparison of each release area of the respective reference products in previous and subsequent studies can be used to obtain a correction factor that takes into account the differences between studies.

Clinical research according to the present invention refers to research conducted in full compliance with the International Conference for Harmonization of Clinical Trials (ICH) and all applicable local Good Clinical Practices (GCP) and regulations.

Within the meaning of the present invention, the term "healthy human subject" means having a body mass index (BMI) ranging from 55 kg to 100 kg and a body mass index (BMI) ranging from 18 to 29.4 and normal physiological parameters (such as blood pressure, etc.) ) Of male or female subjects. Healthy human subjects for the purposes of the present invention are selected based on and in accordance with the inclusion and exclusion criteria recommended by ICH.

Within the meaning of the present invention, the term "subject population" refers to at least five, preferably at least ten, individual healthy human subjects.

Within the meaning of the present invention, the term "geometric mean" refers to the average value of log-transformed data back-transformed to the original scale.

Within the meaning of the present invention, the term "arithmetic mean" refers to the sum of all observations divided by the total number of observations.

Within the meaning of the present invention, the parameter "AUC" corresponds to the area under the plasma concentration-time curve. The AUC value is proportional to the total amount of active agent absorbed into the blood circulation and is therefore a measure of bioavailability.

Within the meaning of the present invention, the parameter "AUC _t1-t2 " is expressed in (ng / ml) h and relates to the area under the plasma concentration-time curve from the t1 hour to the t2 hour, and in a linear trapezoidal method (linear trapezoidal method) calculations unless otherwise indicated. Other calculation methods are, for example, the logarithmic method and the linear logarithmic trapezoidal method.

Within the meaning of the present invention, the parameter "C _max " is expressed in (ng / ml) and relates to the maximum observed plasma concentration of the active agent.

Within the meaning of the present invention, the parameter " _Ct " is expressed in (ng / ml) and relates to the plasma concentration of the active agent observed at the t-hour.

Within the meaning of the present invention, the parameter "t _max " is denoted by h and relates to the time point at which the C _max value is reached. In other words, t _max is the time point at which the maximum plasma concentration is observed.

Within the meaning of the present invention, the term "average plasma concentration" is expressed in (ng / ml) and is the average of the individual plasma concentrations of the active agent (eg guanfacine) at various time points.

Within the meaning of the present invention, the term "coating composition" refers to the composition of all the components of the matrix layer contained in the solvent, which can be coated on the backing layer or release liner and formed immediately after drying Matrix layer.

Within the meaning of the present invention, the term "pressure-sensitive adhesive composition" refers to a pressure-sensitive adhesive mixed with at least a solvent (for example, n-heptane or ethyl acetate).

Within the meaning of the present invention, the term "dissolve" refers to the process of obtaining a solution that is transparent and does not contain any particles visible to the naked eye.

Within the meaning of the present invention, the term "solvent" refers to any liquid substance, which is preferably a volatile organic liquid such as methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride, hexane, n-heptane , Toluene and its mixture.

TTS structure

The present invention relates to a transdermal therapeutic system for percutaneous administration of guanfacine, which includes a layer structure containing guanfacine, the layer structure containing guanfacine contains a) a backing layer, and b) guanfacine containing Of the layer, wherein the transdermal therapeutic system comprises at least one polysiloxane acrylic hybrid polymer. The guanfacine-containing layer structure is preferably a guanfacine-containing self-adhesive layer structure and preferably does not include an additional skin contact layer. In particular, polysiloxyacrylic hybrid polymers present in transdermal therapeutic systems (preferably in self-adhesive layer structures) preferably provide adhesive properties.

The TTS according to the present invention may be a matrix-type TTS or a reservoir-type TTS, and is preferably a matrix-type TTS.

In the matrix-type TTS according to the present invention, guanfacine is preferably uniformly dispersed in a polymer carrier (ie, matrix), which forms a matrix layer with guanfacine and optionally the remaining components. According to this, in one embodiment of the present invention, the guanfacine-containing layer may be a guanfafaxin-containing matrix layer, wherein the guanfacine is uniformly dispersed in the polymer matrix. The polymer matrix preferably contains at least one polysiloxane acrylic hybrid polymer. Therefore, according to the present invention, it is preferable that the guanfacine-containing matrix layer contains guanfacine and the polysiloxyacrylic hybrid polymer present in the TTS. In this regard, it is preferred that the guanfacine-containing matrix layer is self-adhesive, so no additional skin contact layer is present. If the substrate layer containing guanfacine is prepared by laminating two substrate layers containing guanfacine with substantially the same composition, the resulting double layer is regarded as a substrate layer containing guanfacine .

In the reservoir-type TTS according to the present invention, the guanfacine-containing layer is a guanfacine-containing reservoir layer, which preferably contains a liquid reservoir that contains guanfacine. The reservoir type TTS typically additionally includes a skin contact layer, where the reservoir layer and the skin contact layer are preferably separated by a rate control membrane. Polysiloxane-acrylic hybrid polymers provide adhesive properties. Preferably, the skin contact layer is made so as to be free of guanfacine.

In a preferred embodiment of the present invention, the guanfacine-containing layer is a guanfafaxin-containing matrix layer, which includes
i) guanfacine, and
ii) At least one polysiloxane acrylic hybrid polymer.

Therefore, according to an embodiment, the present invention relates to a transdermal therapeutic system for percutaneous administration of guanfacine, which includes a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising:
A) Backing layer; and
B) A layer containing guanfacine, which is preferably a matrix layer containing guanfacine, which comprises:
i) guanfacine, and
ii) At least one polysiloxane acrylic hybrid polymer.

The layer structure containing guanfacine is preferably a self-adhesive layer structure containing guanfacine. In this respect, it is also preferable that the layer structure containing guanfacine does not include an additional skin contact layer. Instead, it is preferred that the guanfacine-containing layer (which is preferably a guanfacine-containing matrix layer) is self-adhesive. Therefore, in a preferred embodiment, the layer structure containing guanfacine is a self-adhesive layer structure containing guanfacine and preferably does not include an additional skin contact layer. Alternatively or additionally, it is preferred that the guanfacine-containing layer is directly attached to the backing layer, so there is no additional layer between the backing layer and the guanfacine-containing layer. As a result, a layer structure of low complexity is obtained, which is advantageous in terms of manufacturing cost.

In particular, it is preferred that the layer structure containing guanfacine contains no more than 3 layers, preferably 2 layers, that is, preferably only the backing layer and the layer containing guanfacine. Sufficient adhesion between the self-adhesive layer structure containing guanfacine and the skin of the patient during administration is provided by the layer containing guanfacine (which is preferably the matrix layer containing guanfacine). If an additional skin contact layer is present, for example as the third layer of the guanfacine-containing layer structure, the adhesive properties can be provided by the additional skin contact layer. However, it is preferred according to the invention that no additional skin contact layer is present.

The self-adhesive properties of the layer structure containing guanfacine are preferably composed of at least one polysilicon present in the TTS (preferably in the layer containing guanfacine and more preferably in the matrix layer containing guanfacine). Provided by oxyacrylic hybrid polymers. Therefore, in a preferred embodiment of the present invention, at least one polysiloxane-based acrylic hybrid polymer is a polysiloxane-based acrylic hybrid pressure-sensitive adhesive. More details about the polysiloxyacrylic hybrid polymer according to the present invention are provided further below.

It should be understood that the TTS according to the present invention contains at least a therapeutically effective amount of guanfacine. Therefore, in a preferred embodiment of the present invention, the layer structure containing guanfacine contains a therapeutically effective amount of guanfacine. The guanfacine in the guanfafaxin-containing layer structure is preferably present as a free base, which is preferably dispersed in the guanfafaxin-containing layer. The preferred embodiment of guanfacine in the TTS according to the present invention is further provided below.

According to the invention it is preferred that the release area of the TTS ranges from 1 to 100 cm ² , preferably from 2.5 to 50 cm ² .

In a preferred embodiment of the present invention, the backing layer is substantially impermeable to guanfacine. Furthermore, it is preferred that the backing layer is closed, as described above.

According to some embodiments of the present invention, the TTS may additionally include an adhesive cover layer. The adhesive cover layer is larger in area than the guanfacine-containing layer structure and is attached to it to enhance the adhesive properties of the entire transdermal therapeutic system. The adhesive cover layer includes a backing layer and an adhesive layer. The adhesive cover provides additional areas that adhere to the skin but do not count into the area of guanfacine release. The adhesive cover layer comprises a self-adhesive polymer or a self-adhesive polymer mixture selected from the group consisting of: polysiloxane-based acrylic hybrid polymer, acrylate polymer, polysiloxane polymer, polyisobutylene, styrene- The isoprene-styrene copolymer, and mixtures thereof, may be the same as or different from any polymer or polymer mixture included in the guanfacine-containing layer structure.

The layer structure containing guanfacine (such as a self-adhesive layer structure containing guanfacine) according to the present invention is usually located on a detachable protective layer (release liner), which is applied just to the surface of the patient's skin Removed before. Therefore, the TTS may additionally include a release liner. TTS protected in this way is usually stored in blister packs or seam-sealed pouches. The packaging may be child resistant and / or senior friendly.

Guanfacine-containing layer

As outlined in more detail above, the TTS according to the present invention includes a layer structure containing guanfacine, which includes a layer containing guanfacine. Preferably, the layer structure containing guanfacine is a self-adhesive layer structure containing guanfacine. According to this, it is also preferable that the guanfacine-containing layer is a self-adhesive guanfacine-containing layer, and more preferably a self-adhesive guanfacine-containing matrix layer. In a preferred embodiment, the guanfacine-containing layer contains a therapeutically effective amount of guanfacine.

In one embodiment of the present invention, the layer containing guanfacine is a matrix layer containing guanfacine. In another embodiment, the guanfacine-containing layer is a guanfacine-containing reservoir layer. Preferably, the layer containing guanfacine is a matrix layer containing guanfacine.

In one embodiment, the guanfacine-containing layer includes:
i) Guanfacine, preferably in free base form; and
ii) At least one polysiloxane acrylic hybrid polymer.
It should be understood that the at least one polysiloxane acrylic hybrid polymer contained in the guanfacine-containing layer is at least one polysiloxane acrylic hybrid polymer, which is included in the TTS according to the present invention.

In a preferred embodiment, the layer containing guanfacine is a matrix layer containing guanfacine, which comprises
i) Guanfacine, preferably in free base form; and
ii) At least one polysiloxane acrylic hybrid polymer.
It should be understood that the at least one polysiloxane acrylic hybrid polymer contained in the guanfacine-containing layer is at least one polysiloxane acrylic hybrid polymer, which is included in the TTS according to the present invention.

In a preferred embodiment, the guanfacine-containing layer includes at least one polysiloxane-based acrylic hybrid polymer, which is a polysiloxane-based acrylic hybrid pressure-sensitive adhesive. Therefore, the guanfacine-containing layer is preferably a guanfacine-containing matrix layer, and particularly preferably a guanfacine-containing pressure-sensitive adhesive matrix layer.

In one embodiment of the present invention, the guanfacine-containing layer can be obtained by dispersing guanfacine (preferably in the form of a free base). As a result, the guanfacine-containing layer of the TTS according to the present invention generally contains guanfacine in the form of a free base. In addition, in some embodiments of the present invention, guanfacine may partially exist in a protonated form. However, it is preferred that at least 50 mol% of guanfacine in the guanfacine-containing layer, preferably at least 75 mol%, is present as the free base. In a particularly preferred embodiment, at least 90 mol% of guanfacine in the guanfacine-containing layer, preferably at least 95 mol%, more preferably at least 99 mol% is in the form of free base.

In one embodiment of the present invention, the guanfacine-containing layer structure of the transdermal therapeutic system (preferably the guanfacine-containing layer according to the present invention, and more preferably the guanfacine-containing matrix layer) includes the guanidine method The amount of Xin is from 1 to 100 mg / TTS, preferably from 8 to 72 mg / TTS. In a preferred embodiment, the layer structure containing guanfacine (preferably a layer containing guanfacine, more preferably a matrix layer containing guanfacine) contains from 8 to 30 mg / TTS, for example from 8 Guanfacine to 10 mg / TTS or from 17 to 19 mg / TTS. In other words, the total amount of guanfacine in the layer structure containing guanfacine ranges from 1 to 100 mg / TTS, preferably from 8 to 72 mg / TTS, more preferably from 8 to 30 mg / TTS, for example From 8 to 10 mg / TTS or from 17 to 19 mg / TTS.

In another embodiment, the loading of guanfacine in the layer structure containing guanfacine ranges from 0.2 to 1.6 mg / cm ² , preferably from 0.4 to 1.2 mg / cm ² . In addition, it is preferable that the release area of TTS ranges from 1 to 100 cm ² , preferably from 2.5 to 50 cm ² .

In one embodiment of the present invention, the content of guanfacine in the guanfafaxin-containing layer is from 1 to 20% by weight based on the total weight of the guanfafaxin-containing layer, preferably from 3 to 16 % By weight, more preferably from 4 to 14% by weight, most preferably from 5 to 13% by weight. Particularly preferably, the content of guanfacine in the guanfacine-containing layer is from 4 to 8% by weight based on the total weight of the guanfacine-containing layer, preferably from 5 to 7% by weight, or the amount thereof From 10 to 14% by weight, preferably from 11 to 13% by weight, the content depends on the desired administration strength of TTS.

The layer structure containing guanfacine (preferably a layer containing guanfacine) comprises at least one polysilicoxyacrylic hybrid polymer. As explained above, the polysiloxane-acrylic hybrid polymer contains a polysiloxane phase and an acrylate phase, the preferred weight ratio is from 60:40 to 40:60, and the optimal weight ratio is 50:50. Polysiloxane-acrylic hybrid polymers usually contain the following reaction products: (a) polysiloxane-containing pressure-sensitive adhesive composition, which contains acrylate or methacrylate functionality, (b) ethylenic unsaturated Monomer; and (c) starter. More details about components (a), (b) and (c) are provided further below. It should be understood that component (a) mainly forms the polysiloxane phase of the polysiloxane acrylic hybrid polymer, and component (b) mainly forms the acrylate phase of the polysiloxane acrylic hybrid polymer. The acrylate phase affects the viscosity and viscosity of the polysiloxane-acrylic hybrid polymer. Therefore, it is preferable that the ethylenically unsaturated monosystem forming the acrylate phase is a combination of 2-ethylhexyl acrylate and methyl acrylate, preferably in a ratio of 40:60 to 70:30. In terms of high adhesion, the ratio of 60:40 is preferred, although the viscosity is therefore lower. In terms of high viscosity, the 50:50 ratio is preferred, although the adhesiveness is reduced. The polysiloxane-acrylic hybrid polymer in the guanfacine-containing layer preferably contains a continuous acrylic outer phase and a discontinuous polysiloxane inner phase.

In one embodiment of the present invention, the guanfacine-containing layer includes at least one polysilicoxyacrylic hybrid polymer in an amount of from 20 to 99% based on the total weight of the guanfacine-containing layer, It is preferably from 30 to 97%, most preferably from 35 to 94% by weight. In a preferred embodiment, the guanfacine-containing layer contains at least one polysilicoxyacrylic hybrid polymer in an amount of from 74 to 94% by weight based on the total weight of the guanfacine-containing layer. It is preferably 74 to 89% by weight. It should be understood that the amount of at least one polysiloxane acrylic hybrid polymer indicated above may refer to one polysiloxane acrylic hybrid polymer, but may also be a combination of several polysiloxane acrylic hybrid polymers. Therefore, the amount given refers to the total amount of polysiloxane acrylic mixed polymer.

In a preferred embodiment of the present invention, the guanfacine-containing layer contains only one polysiloxane-acrylic-acrylic hybrid polymer in an amount of from 60 to 97 based on the total weight of the guanfacine-containing layer The amount by weight is preferably from 70 to 94% by weight.

In another preferred embodiment of the present invention, the guanfacine-containing layer includes a first polysiloxane acrylic hybrid polymer and a second polysiloxane acrylic hybrid polymer, wherein the at least two polysiloxanes The total amount of the acrylic hybrid polymer is from 35 to 94% by weight, preferably from 74 to 94% by weight, based on the total weight of the guanfacine-containing layer. Preferably, the guanfacine-containing layer contains a first polysiloxyacrylic hybrid polymer in an amount of from 60 to 90% by weight based on the total weight of the guanfacine-containing layer, and the second polysilicon The oxyacrylic-based hybrid polymer is used in an amount of from 1 to 10% by weight based on the total weight of the guanfacine-containing layer. In a particularly preferred embodiment, the guanfacine-containing layer comprises a first polysiloxane-based acrylic hybrid polymer in an amount of from 70 to 78% by weight based on the total weight of the guanfacine-containing layer. Preferably from 73 to 75% by weight, and the second polysiloxane-acrylic hybrid polymer, the amount of which is based on the total weight of the layer containing guanfacine from 1 to 8% by weight, preferably from 3 to 5 weight%. In another particularly preferred embodiment, the guanfafaxin-containing layer includes a first polysiloxane-based acrylic hybrid polymer in an amount of from 77 to 85% by weight based on the total weight of the guanfafaxin-containing layer. , Preferably from 79 to 83% by weight, and the second polysiloxane-acrylic hybrid polymer, the amount of which is based on the total weight of the layer containing guanfacine from 1 to 8% by weight, preferably from 3 to 5 wt%.

It should be understood that the above instructions pertain to polysiloxane-acrylic hybrid polymers, in particular, the weight ratio of acrylate to polysiloxane phase, the components forming polysiloxane-acrylic hybrid polymers, and the formation of polysilicon The ethylenically unsaturated monomers of the oxyacrylic hybrid polymer, as well as the preferences for the acrylic external phase and the polysiloxane internal phase, are applicable to both the first and second polysiloxane acrylic hybrid polymers. In particular, it is preferable that the weight ratio of polysiloxane to the acrylate phase in the first polysiloxane-based acrylic hybrid polymer is from 55:45 to 45:55, and the ethylenically unsaturated monomer forming the acrylate The body contains 2-ethylhexyl acrylate and methyl acrylate in a ratio from 55:45 to 45:55. More preferably, the weight ratio of polysiloxane to the acrylate phase in the first polysiloxane-based acrylic hybrid polymer is 50:50, and the ethylenically unsaturated monomer forming the acrylate contains a ratio of 50:50 2-ethylhexyl acrylate and methyl acrylate. On the other hand, it is preferred that the weight ratio of polysiloxane to the acrylate phase in the second polysiloxane-acrylic hybrid polymer is from 55:45 to 45:55, and the ethylenic unsaturated forming acrylate The monomer contains 2-ethylhexyl acrylate and methyl acrylate in a ratio from 65:35 to 55:45. More preferably, the weight ratio of polysiloxane to the acrylate phase in the second polysiloxane-acrylic hybrid polymer is 50:50, and the acrylate-forming ethylenically unsaturated monomer includes a ratio of 60:40 Of 2-ethylhexyl acrylate and methyl acrylate. In addition, for the polysiloxane-acrylic hybrid polymer, it is preferred that the polysiloxane phase is the internal phase and the acrylate phase is the external phase.

It should be understood that the TTS (especially the guanfacine-containing layer) according to the present invention may further include at least one non-hybrid polymer, preferably at least one non-hybrid pressure, in addition to the polysiloxane-acrylic hybrid polymer. Sensitive adhesive. Exemplarily, the non-hybrid polymer (or non-hybrid pressure-sensitive adhesive) contains polysiloxane (ie polysiloxane polymer, also known as polysiloxane), acrylate polymer (also known as acrylate) , Polyisobutylene, or styrene-isoprene-styrene block copolymer. In one embodiment of the present invention, the non-hybrid polymer is a pressure sensitive adhesive based on polysiloxane or acrylate. Therefore, according to the present invention, it is preferable that the guanfacine-containing layer further contains at least one non-hybrid polymer selected from the group consisting of polysiloxane and acrylate. The preferred options for these polymers are further defined below. Additional polymers can be added to enhance adhesion and / or adhesion.

In some embodiments of the present invention, the guanfacine-containing layer further comprises at least one non-hybrid polymer in an amount of from 5 to 50%, preferably based on the total weight of the guanfacine-containing layer. From 20 to 40% by weight. It should be understood that in addition to at least one polysiloxane acrylic hybrid polymer, there is also at least one non-hybrid polymer, and the total polymer content in the guanfacine-containing layer is the same as the guanfafaxin-containing layer. The total weight is preferably from 70 to 99% by weight, preferably from 75 to 97% by weight. In other words, if at least one non-hybrid polymer is present in addition to the polysiloxane-acrylic hybrid polymer, the guanfacine-containing layer preferably includes the total weight of the guanfacine-containing layer as a reference It is calculated from 20 to 94% by weight, preferably from 35 to 77% by weight of at least one polysiloxane acrylic hybrid polymer.

In some embodiments of the present invention, the guanfacine-containing layer includes at least one polysilicoacrylic blend in a weight ratio of from 10: 1 to 1: 2 (preferably from 2: 1 to 1: 2) The polymer and at least one non-hybrid polymer.

In one embodiment of the invention, the TTS (and in particular the guanfacine-containing layer) according to the invention contains at least one additive. Suitable additives are described in further detail below and preferably have a content of from 0.5 to 10% by weight or from 1 to 10% by weight based on the total weight of the guanfacine-containing layer.

In a preferred embodiment, the guanfacine-containing layer contains at least one additive selected from the group consisting of: a dispersant, a penetration enhancer, and a co-solvent. In a preferred embodiment, the content of the at least one additive (ie, each individual additive) is from 0.5 to 10% by weight or from 1 to 10% by weight based on the total weight of the guanfacine-containing layer. In a preferred embodiment, the at least one additive is a dispersant. In another preferred embodiment, the at least one additive is a penetration enhancer. In yet another preferred embodiment, the at least one additive is a co-solvent. In a preferred embodiment, the combination of the aforementioned additives is also preferred, such as a combination of a dispersant and a penetration enhancer, or a combination of a dispersant and a co-solvent, or a combination of a penetration enhancer and a co-solvent, or a dispersant , A combination of penetration enhancers and co-solvents. The aforementioned additives are particularly advantageous for providing guanfacine in a uniformly dispersed and releasable form. It should be understood that the dispersant can also act as a penetration enhancer, and vice versa. Likewise, co-solvents can additionally act as dispersants or penetration enhancers. In addition, the co-solvent can stabilize the guanfacine dispersion in TTS and avoid crystallization. Moreover, the co-solvent can help to optimize the adhesion of TTS. In certain preferred embodiments, the guanfacine-containing layer contains at least one dispersant and at least one penetration enhancer, and optionally also at least one co-solvent.

In a preferred embodiment, the at least one additive is a dispersant, and its content is from 1 to 10% by weight based on the total weight of the guanfacine-containing layer. Preferably, the content of the dispersant is from 2 to 6% by weight, more preferably from 3 to 5% by weight, based on the total weight of the guanfacine-containing layer.

In another preferred embodiment, the at least one additive is a penetration enhancer, and its content is from 1 to 10% by weight based on the total weight of the guanfacine-containing layer. Preferably, the content of the penetration enhancer is from 2 to 9% by weight, more preferably from 3 to 5% by weight, based on the total weight of the guanfacine-containing layer.

In another embodiment, the at least one additive is a co-solvent, and its content is from 0.5 to 10% by weight based on the total weight of the guanfacine-containing layer. Preferably, the co-solvent content is from 0.5 to 4% by weight, more preferably 0.5 to 3% by weight, based on the total weight of the guanfacine-containing layer.

In one embodiment, the TTS according to the invention (and in particular the guanfacine-containing layer, more particularly the guanfacine-containing matrix layer) contains at least two additives selected from the group consisting of: dispersion Agents, penetration enhancers, and co-solvents.

In a preferred embodiment, the transdermal therapeutic system (and in particular the layer containing guanfacine, more particularly the matrix layer containing guanfacine) contains at least two additives, wherein the first additive is a dispersant and its content From 1 to 10% by weight based on the total weight of the guanfacine-containing layer, and the second additive is a penetration enhancer whose content is from 1 to 10 based on the total weight of the guanfacine-containing layer weight%. Preferably, the content of the dispersant is from 1 to 6% by weight, and the content of the penetration enhancer is from 2 to 9% by weight. More preferably, the content of the dispersant is from 3 to 5% by weight, and the content of the penetration enhancer is from 3 to 5% by weight.

In another preferred embodiment, the transdermal therapeutic system (and in particular the layer containing guanfacine, more particularly the matrix layer containing guanfacine) contains at least two additives, wherein the first additive is a dispersant, Its content is from 1 to 10% by weight based on the total weight of the guanfacine-containing layer, and the second additive is a co-solvent, and its content is from 0.5 to 0.5% 10% by weight. Preferably, the content of the dispersant is from 1 to 6% by weight, and the content of the co-solvent is from 0.5 to 4% by weight. More preferably, the content of the dispersant is from 3 to 5% by weight, and the content of the co-solvent is from 0.5 to 3% by weight.

In another preferred embodiment, the transdermal therapeutic system (and especially the guanfacine-containing layer, more particularly the guanfacine-containing matrix layer) contains at least two additives, wherein the first additive is a penetration enhancer , Its content is from 1 to 10% by weight based on the total weight of the layer containing guanfacine, and the second additive is a co-solvent, its content is from 0.5 based on the total weight of the layer containing guanfacine Up to 10% by weight. Preferably, the content of the penetration enhancer is from 2 to 9% by weight, and the content of the co-solvent is from 0.5 to 4% by weight. Preferably, the content of the penetration enhancer is from 3 to 5% by weight, and the content of the co-solvent is from 0.5 to 3% by weight.

In one embodiment, the TTS according to the invention (and in particular the guanfacine-containing layer, more particularly the guanfacine-containing matrix layer) contains at least three additives selected from the group consisting of: dispersants , Penetration enhancer, and co-solvent.

In one embodiment, the transdermal therapeutic system (and in particular the layer containing guanfacine, more particularly the matrix layer containing guanfacine) contains at least three additives, wherein the first additive is a dispersant, the content of which is The total weight of the guanfacine layer is 1 to 10% by weight, the second additive is a penetration enhancer, and its content is 1 to 10% by weight based on the total weight of the layer containing guanfacine. The third additive is a co-solvent, and its content is 0.5 to 10% by weight based on the total weight of the guanfacine-containing layer. Preferably, the content of the dispersant is 1 to 6% by weight, the content of the penetration enhancer is 2 to 9% by weight, and the content of the co-solvent is 0.5 to 4% by weight. More preferably, the content of the dispersant is 3 to 5% by weight, the content of the penetration enhancer is 3 to 5% by weight, and the content of the co-solvent is 0.5 to 3% by weight.

For the above-mentioned embodiments regarding the number of additives and the amount of additives in the TTS according to the present invention (particularly the layer containing guanfacine, more particularly the matrix layer containing guanfacine), the following specific additives are preferred .

In a preferred embodiment, the dispersant is selected from the group consisting of: esters of fatty acids and polyols, fatty alcohols, polyethylene glycol having a number average molecular weight of from 300 to 400, polyethylene glycol alkanes Ether, and wherein the dispersant is preferably a polyethylene glycol C ₈ -C ₂₀ -alkyl ether having 2 to 10 EO units (preferably from 2 to 6 EO units). A particularly good dispersant is polyoxyethylene (4) lauryl ether (C ₁₂ H ₂₅ (OCH ₂ CH ₂ ) ₄ OH). This dispersant is available for example from Merck under the brand name Brij L4®.

In a preferred embodiment, the penetration enhancer is selected from the group consisting of diethylene glycol monoethyl ether (transcutol), oleic acid, fructose-derived acid, caprylic / capric triglyceride ), Diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, glycerol triacetate, dimethyl propyl urea, and oleyl alcohol, and preferably oil alcohol. Oleitol is available from BASF under the trade name Kollicream® OA, for example.

In a preferred embodiment, the co-solvent is selected from the group consisting of copolymers derived from esters of acrylic acid and methacrylic acid, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer And polyvinyl-caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers. Preferably, the cosolvent is selected from polyvinylpyrrolidone and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. A particularly good cosolvent is a graft copolymer of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol. A suitable polyvinyl-caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is, for example, available from BASF under the trade name Soluplus®, and preferably has the following structural formula, where l, m and n are selected, The average molecular weight measured by gel permeation chromatography is in the range of 90,000 to 140,000 g / mol.

In certain preferred embodiments, the guanfacine-containing layer contains at least one dispersant (the amount thereof is from 2 to 6% by weight), at least one penetration enhancer (the amount is from 2 to 9% by weight), And optionally at least one co-solvent (the amount of which is from 0.5 to 4% by weight), in each case based on the total weight of the guanfacine-containing layer. Preferably, the guanfacine-containing layer contains at least one dispersant (the amount thereof is from 3 to 5% by weight), at least one penetration enhancer (the amount is from 3 to 5% by weight), and optionally at least one auxiliary The solvent (the amount of which is from 0.5 to 3% by weight) is based on the total weight of the guanfacine-containing layer in each case. Regarding the above-mentioned preferred weight% amounts, the above-mentioned preferred dispersants, penetration enhancers and co-solvents are preferred.

Accordingly, in a particularly preferred embodiment, the guanfacine-containing layer contains polyethylene glycol C ₈ -C ₂₀ -alkyl ethers having from 2 to 10 EO units, preferably polyoxyethylene (4) laurel Ether (the amount of which is from 2 to 6% by weight), oleyl alcohol (the amount of which is from 2 to 9% by weight), and optionally polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymerization Substances (the amount of which is from 0.5 to 4% by weight), preferably as specified above, in each case based on the total weight of the guanfacine-containing layer. Most preferably, the guanfacine-containing layer contains polyethylene glycol C ₈ -C ₂₀ -alkyl ether (preferably polyoxyethylene (4) lauryl ether) having from 2 to 10 EO units (the amount of which is from 3 To 5% by weight), oleyl alcohol (the amount of which is from 3 to 5% by weight), and optionally a graft copolymer of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol (the amount of which is from 0.5 To 3% by weight), preferably as specified above, in each case based on the total weight of the guanfacine-containing layer.

In one embodiment of the present invention, the area weight of the layer containing guanfacine ranges from 40 to 250 g / m ² , preferably from 50 to 180 g / m ² , more preferably from 70 to 180 g / m ² , For example from 75 to 150 g / m ² or from 100 to 150 g / m ² . In some preferred embodiments, the area weight ranges from 80 to 120 g / m ² , preferably from 90 to 100 g / m ² .

In view of the above, in one embodiment, the present invention relates to a transdermal therapeutic system for percutaneous administration of guanfacine, which includes a layer structure containing guanfacine, the layer structure including:
A) Backing layer; and
B) A layer containing guanfacine, preferably a matrix layer containing guanfacine, which contains
i) Guanfacine, the amount of which is from 3 to 13% by weight based on the total weight of the layer containing guanfacine;
ii) at least one polysiloxane acrylic hybrid polymer in an amount of from 74 to 89% by weight based on the total weight of the guanfacine-containing layer;
iii) at least one dispersant, the amount of which is from 2 to 6% by weight based on the total weight of the guanfacine-containing layer;
iv) at least one penetration enhancer in an amount of from 2 to 6% by weight based on the total weight of the guanfacine-containing layer; and
v) Optionally at least one co-solvent in an amount of from 0.5 to 4% by weight based on the total weight of the guanfacine-containing layer.
Regarding this embodiment, it is more preferable that the layer structure containing guanfacine does not include an additional skin contact layer. Therefore, the guanfacine-containing layer (preferably the guanfacine-containing matrix layer) preferably represents the skin contact layer and has a pressure-sensitive adhesive property due to the polysiloxyacrylic hybrid polymer.

In a preferred embodiment, the layer containing guanfacine is a matrix layer containing guanfacine, which comprises
i) Guanfacine, the amount of which is from 3 to 13% by weight;
ii) at least one polysiloxane acrylic hybrid polymer in an amount of from 74 to 89% by weight based on the total weight of the guanfacine-containing layer;
iii) Polyethylene glycol C ₈ -C ₂₀ -alkyl ether having from 2 to 10 EO units, the amount of which is from 2 to 6% by weight based on the total weight of the guanfacine-containing layer;
iv) oleyl alcohol, the amount of which is from 2 to 6% by weight based on the total weight of the guanfacine-containing layer; and
v) Optionally, a graft copolymer of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol, the amount of which is from 0.5 to 4% by weight based on the total weight of the guanfacine-containing layer.

In a particularly preferred embodiment, the layer containing guanfacine is a matrix layer containing guanfacine, which contains
i) guanfacine, the amount of which is from 11 to 13% by weight based on the total weight of the guanfacine-containing layer;
ii) The first polysiloxyacrylic hybrid polymer whose amount is from 73 to 75% by weight based on the total weight of the guanfacine-containing layer, and the second polysiloxyacrylic hybrid polymer whose amount From 3 to 5% by weight based on the total weight of the guanfacine-containing layer;
iii) Polyethylene glycol C ₈ -C ₂₀ -alkyl ethers having from 2 to 10 EO units, preferably polyoxyethylene (4) lauryl ether, the amount of which is based on the total weight of the layer containing guanfacine From 3 to 5% by weight;
iv) oleyl alcohol, the amount of which is from 3 to 5 wt% based on the total weight of the guanfacine-containing layer; and
v) Polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, the amount of which is from 0.5 to 3% by weight based on the total weight of the guanfacine-containing layer.
Regarding this embodiment, the preferred options regarding the first and second polysiloxane-based acrylic hybrid polymers as outlined above are also preferred. In particular, it is preferred that the weight ratio of polysiloxane to the acrylate phase in the first polysiloxane-based acrylic hybrid polymer is from 55:45 to 45:55, preferably about 50:50, and The acrylate-forming ethylenically unsaturated monomer comprises 2-ethylhexyl acrylate and methyl acrylate in a ratio from 55:45 to 45:55, preferably about 50:50. In addition, it is preferred that the weight ratio of polysiloxane to the acrylate phase in the second polysiloxane-acrylic hybrid polymer is from 55:45 to 45:55, preferably about 50:50, and acrylic acid is formed The ethylenically unsaturated monomer of the ester contains 2-ethylhexyl acrylate and methyl acrylate in a ratio from 65:35 to 55:45, preferably 60:40. In addition, for the two polysiloxane-acrylic hybrid polymers, it is preferred that the polysiloxane phase is the internal phase and the acrylate phase is the external phase. Furthermore, it is preferred that the area weight of the guanfacine-containing layer ranges from 80 to 120 g / m ² , preferably from 90 to 100 g / m ² .

In another particularly preferred embodiment, the layer containing guanfacine is a matrix layer containing guanfacine, which contains
i) Guanfacine, the amount of which is from 5 to 7 wt% based on the total weight of the layer containing guanfacine;
ii) The first polysiloxane-acrylic hybrid polymer, the amount of which is from 79 to 83% by weight based on the total weight of the guanfacine-containing layer, and the second polysiloxane-acrylic hybrid polymer, the amount From 3 to 5% by weight based on the total weight of the guanfacine-containing layer;
iii) Polyethylene glycol C ₈ -C ₂₀ -alkyl ether with 2 to 10 EO units, preferably polyoxyethylene (4) lauryl ether, based on the total weight of the layer containing guanfacine From 3 to 5% by weight; and
iv) Oleyl alcohol in an amount of from 3 to 5 wt% based on the total weight of the guanfacine-containing layer.
Regarding this embodiment, the preferred options regarding the first and second polysiloxane-based acrylic hybrid polymers as outlined above are also preferred. In particular, it is preferred that the weight ratio of polysiloxane to the acrylate phase in the first polysiloxane-based acrylic hybrid polymer is from 55:45 to 45:55, preferably about 50:50, and The acrylate-forming ethylenically unsaturated monomer comprises 2-ethylhexyl acrylate and methyl acrylate in a ratio from 55:45 to 45:55, preferably about 50:50. In addition, it is preferred that the weight ratio of polysiloxane to the acrylate phase in the second polysiloxane-acrylic hybrid polymer is from 55:45 to 45:55, preferably about 50:50, and acrylic acid is formed The ethylenically unsaturated monomer of the ester contains 2-ethylhexyl acrylate and methyl acrylate in a ratio from 65:35 to 55:45, preferably 60:40. In addition, for the two polysiloxane-acrylic hybrid polymers, it is preferred that the polysiloxane phase is the internal phase and the acrylate phase is the external phase. Furthermore, it is preferred that the area weight of the guanfacine-containing layer ranges from 80 to 120 g / m ² , preferably from 90 to 100 g / m ² .

Guanfacine

The TTS according to the present invention includes a guanfacine-containing layer structure comprising: A) a backing layer; and B) a guanfacine-containing layer; wherein the transdermal therapeutic system comprises at least one polymer Silicone acrylic mixed polymer. The guanfacine-containing layer, which is preferably a guanfacine-containing matrix layer, has been described in detail above.

In one embodiment of the present invention, the amount of guanfacine contained in the layer structure containing guanfacine ranges from 1 to 100 mg / TTS, preferably from 8 to 72 mg / TTS, and more preferably from 8 to 30 mg / TTS, for example from 8 to 10 mg / TTS or from 17 to 19 mg / TTS. More details in this regard have been provided above.

In one embodiment of the present invention, the guanfacine-containing layer structure preferably contains a therapeutically effective amount of guanfacine. More preferably, a therapeutically effective amount of guanfacine is present in the guanfacine-containing layer of the guanfacine-containing layer structure. Preferably, the guanfacine in the layer structure containing guanfacine is in the form of free base.

In one embodiment of the present invention, at least 50 mol%, preferably at least 75 mol% of the total amount of guanfacine in the TTS is in the form of free base. In a particularly preferred embodiment, the total amount of guanfacine in the TTS is at least 90 mol%, preferably at least 95 mol%, more preferably at least 99 mol% in the form of free base. Therefore, it is preferred that at least 50 mol%, preferably at least 75 mol% of guanfacine in the guanfacine-containing layer is present as a free base. In a particularly preferred embodiment, at least 90 mol%, preferably at least 95 mol%, and more preferably at least 99 mol% of guanfacine in the guanfacine-containing layer is present as a free base. In some embodiments, the guanfacine-containing layer does not contain guanfacine salt.

In some embodiments, the amount of guanfacine in the guanfacine-containing layer ranges from 1 to 20% by weight, preferably from 3 to 16% by weight, based on the total weight of the guanfafaxin-containing layer , Preferably from 5 to 13% by weight, for example from 11 to 13% by weight or from 5 to 7% by weight.

In one embodiment of the present invention, the guanfacine-containing layer can be obtained by dispersing guanfacine in the form of free base. If the guanfacine-containing layer is a guanfafaxin-containing matrix layer, the layer is preferably dispersed by dispersing guanfacine in the form of a free base on a polymer carrier (especially including polysilicoxyacrylic It is obtained by blending a polymer, and optionally at least one additive as described above, especially at least one dispersant).

In one embodiment, the guanfacine-containing layer comprises guanfacine pharmaceutically acceptable salts, such as guanfacine hydrochloride or guanfacine hydrochloride, preferably guanfacine hydrochloride. However, according to the present invention, it is preferred that the guanfacine in the guanfacine-containing layer exists as a free base.

In certain embodiments, guanfacine has a purity of at least 95%, preferably at least 98%, and more preferably at least 99%, as determined by quantitative HPLC. Quantitative HPLC can be performed by reverse phase HPLC with UV detection.

Silicone acrylic mixed polymer

The TTS according to the present invention contains a polysiloxane acrylic hybrid polymer. The polysiloxane-acrylic hybrid polymer includes a polymerized hybrid species, and the polymerized hybrid species includes a polysiloxane-based subclass and an acrylate-based subclass that have been polymerized together. The polysiloxane-acrylic hybrid polymer therefore contains a polysiloxane phase and an acrylic phase. Preferably, the polysiloxane-based acrylic hybrid polymer is a polysiloxane-based acrylic hybrid pressure-sensitive adhesive.

Polysiloxane acrylic mixed pressure-sensitive adhesives are usually supplied and used in solvents (such as n-heptane and ethyl acetate). The solid content of pressure-sensitive adhesives is usually between 30% and 80%. The skilled person knows that the solid content can be changed by adding an appropriate amount of solvent.

Preferably, the weight ratio of polysiloxane to acrylate in the polysiloxane-acrylic mixed pressure-sensitive adhesive is from 5:95 to 95: 5, or from 20:80 to 80:20, more preferably from 40 : 60 to 60: 40, and the best polysiloxane to acrylate ratio is about 50: 50. A suitable polysiloxane-acrylic hybrid pressure-sensitive adhesive with a weight ratio of polysiloxane to acrylate of 50:50 is, for example, a commercially available polysiloxane-acrylic hybrid pressure-sensitive adhesive 7-6102 (polysiloxane / Acrylate ratio 50/50) and 7-6302 (polysiloxane / acrylate ratio 50/50), supplied by Dow Corning in ethyl acetate.

The preferred polysiloxane-acrylic hybrid pressure-sensitive adhesives according to the invention are characterized by a solution viscosity of about 50% solids content in ethyl acetate at 25 ° C and greater than about 400 cP, or from about 500 cP To about 3,500 cP, especially from about 1,000 cP to about 3,000 cP, more preferably from about 1,200 cP to about 1,800, or most preferably about 1,500 cP, or even more preferably from about 2,200 cP to about 2,800 cP, or most Preferably it is about 2,500 cP, preferably measured at 50 RPM using a Brookfield RVT viscometer equipped with a No. 5 rotor.

The characteristics of these polysiloxane-acrylic hybrid pressure-sensitive adhesives may also be a complex viscosity of 0.1 rad / s at 30 ° C of less than about 1.0e9 poise, or from about 1.0e5 poise to about 9.0e8 poise, or More preferably, it is from about 9.0e5 to about 1.0e7, or most preferably about 4.0e6, or more preferably from about 2.0e6 to about 9.0e7, or most preferably about 1.0e7, preferably A Rheometrics ARES rheometer was used, where the rheometer was equipped with an 8mm plate and the gap was zeroed.

To prepare a sample for measuring the rheological behavior using a Rheometrics ARES rheometer, the adhesive solution between 2 and 3 grams can be poured on the SCOTCH-PAK 1022 fluoropolymer release liner and allowed to stand in the surrounding environment Set for 60 minutes. To obtain a substantially solvent-free adhesive film, they can be placed in an oven at 110 ° C +/- 10 ° C for 60 minutes. After removing from the oven, let it equilibrate to room temperature. The film can be removed from the release liner and folded to form a square. To eliminate air bubbles, a Carver press can be used to compress the film. The sample can then be loaded between the plates and compressed to 1.5 +/- 0.1 mm at 30 ° C. Trim excess adhesive and record the final gap. The following settings can be used to perform a frequency sweep between 0.01 and 100 rad / s: temperature = 30 ° C; strain = 0.5-1% and data is collected by collecting 3 points every 10 times the gap.

Commercially available suitable polysiloxane acrylic hybrid pressure-sensitive adhesives include PSA series 7-6100 and 7-6300 manufactured by Dow Corning and supplied in n-heptane or ethyl acetate, (7-610X and 7-630X ; X = 1 based on n-heptane / X = 2 based on ethyl acetate). For example, a 7-6102 polysiloxane acrylic mixed PSA with a 50/50 polysiloxane / acrylate ratio is characterized by a solution viscosity of 2,500 cP at 25 ° C and about 50% solids content in ethyl acetate And at 30 ℃, the complex viscosity of 0.1 rad / s is 1.0e7 poise. 7-6302 polysiloxane-acrylic acid system with a polysiloxane / acrylate ratio of 50/50 mixed with PSA at 25 ° C and approximately 50% solids content in ethyl acetate has a solution viscosity of 1,500 cP and at 30 ° C The complex viscosity of 0.1 rad / s is 4.0e6 poise.

Depending on the solvent supply of the polysiloxane-acrylic-based mixed pressure-sensitive adhesive, the arrangement of the polysiloxane-acrylic and acrylic phases that provide the polysiloxane- or acrylic-based continuous external phase and the corresponding discontinuous internal phase will be different. If the polysiloxane-acrylic mixed pressure-sensitive adhesive is provided in n-heptane, the composition contains a continuous polysiloxane outer phase and a discontinuous acrylic inner phase. If the polysiloxane-acrylic mixed pressure-sensitive adhesive is provided in ethyl acetate, the composition contains a continuous acrylic external phase and a discontinuous polysiloxane internal phase. After evaporating the solvent supplying the polysiloxane-acrylic acid-based pressure-sensitive adhesive, the phase arrangement of the resulting pressure-sensitive adhesive film or layer corresponds to the phase arrangement of the solvent-containing adhesive coating composition. For example, in the absence of any substance that can cause the phase alignment of the polysiloxyacrylic mixed pressure-sensitive adhesive composition to be reversed, the polysiloxyacrylic mixed in n-heptane can form a pressure-sensitive adhesive The prepared pressure-sensitive adhesive layer provides a continuous polysiloxane outer phase and a discontinuous acrylic inner phase, a pressure-sensitive adhesive layer prepared by mixing a polysiloxane acrylic acid in ethyl acetate with a pressure-sensitive adhesive Provide continuous acrylic external phase and discontinuous polysiloxane internal phase. The phase alignment of the composition can be determined, for example, in a peeling force test using a pressure-sensitive adhesive film or layer made of a polysiloxane-acrylic mixed PSA composition attached to a siliconized release liner. If the siliconized release liner cannot or can hardly be removed from the pressure-sensitive adhesive film (laminated on the backing film) due to the blocking of the two silicone surfaces, the pressure-sensitive adhesive film contains continuous Polysilicon external phase. The barrier is caused by the adhesion of two polysilicon layers containing similar surface energy. The polysiloxane adhesive shows good extension on the siliconized liner, so it can produce good adhesion to the liner. If the siliconized release liner can be easily removed, the pressure-sensitive adhesive film contains a continuous acrylic external phase. Acrylic adhesives do not spread well due to different surface energies and therefore have low or almost no adhesion to silicified liners.

According to a preferred embodiment of the present invention, the polysiloxane-based acrylic hybrid polymer is a polysiloxane-based acrylic resin obtainable from a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality Mixed into pressure-sensitive adhesive. It should be understood that the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality may include only acrylate functionality, only methacrylate functionality, or include acrylate functionality and Both methacrylate functionality.

According to some embodiments of the present invention, the polysiloxyacrylic hybrid pressure-sensitive adhesive comprises (a) a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality, (b) The reaction product of an ethylenically unsaturated monomer and (c) an initiator. That is, the polysiloxane-acrylic mixed pressure-sensitive adhesive is the product of the chemical reaction between these reactants ((a), (b), and (c)). In particular, the polysiloxane-acrylic hybrid pressure-sensitive adhesive includes (a) a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality, (b) (meth) acrylate The monomer, and (c) the reaction product of the initiator (ie, in the presence of the initiator). That is, the polysiloxane-acrylic hybrid pressure-sensitive adhesive includes products of chemical reactions between these reactants ((a), (b), and (c)).

(a) The reaction product of a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality, (b) an ethylenically unsaturated monomer, and (c) an initiator may contain a continuous polymer The silica external phase and the discontinuous acrylic internal phase, or the reaction products of (a), (b), and (c) may contain a continuous acrylic external phase and a discontinuous polysilicon internal phase.

Silicone-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality (a) The content of polysiloxane-based acrylic mixed pressure-sensitive adhesive is usually 100 parts by weight of the mixed pressure-sensitive adhesive The agent is based on 5 to 95 parts by weight, more usually 25 to 75 parts by weight.

The content of the ethylenically unsaturated monomer (b) in the polysiloxane acrylic mixed pressure-sensitive adhesive is generally from 5 to 95 parts by weight based on 100 parts by weight of the mixed pressure-sensitive adhesive, more particularly 25 to 75 parts by weight.

The content of the initiator (c) in the polysiloxane acrylic mixed pressure-sensitive adhesive is generally from 0.005 to 3 parts by weight based on 100 parts by weight of the mixed pressure-sensitive adhesive, more usually from 0.01 to 2 parts by weight.

According to some embodiments of the present invention, a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality (a) comprises (a1) polysiloxane resin, (a2) polysilicon polymerization And (a3) provide the condensation reaction product of the acrylate or methacrylate functional silicon-containing blocking agent. Silicone resin (a1) can also be called silicate resin or silica resin. Preferably, the polysiloxane polymer (a2) is polysiloxane, preferably polydimethylsiloxane. It should be understood that (a1) and (a2) form a polysiloxane-based pressure-sensitive adhesive by polycondensation, and acrylate or methacrylate functionality is introduced by reaction with (a3).

According to some embodiments of the present invention, the silicon-containing pressure-sensitive adhesive composition (a) containing acrylate or methacrylate functionality includes the following condensation reaction products:
(a1) Silicone resin,
(a2) polysiloxane polymer, and
(a3) providing an acrylate or methacrylate functional silicon-containing blocking agent, wherein the silicon-containing blocking agent has the general formula XYR ' _b SiZ _3-b , wherein
X is a monovalent group of the general formula AE-,
Where E is -O- or -NH-, and A is acryl or methacryl,
Y is a divalent alkylene group having from 1 to 6 carbon atoms,
R 'is methyl or phenyl,
Z is a monovalent hydrolyzable organic group or halogen, and
b is 0 or 1;
Wherein the silicone resin and the silicone polymer react to form a pressure-sensitive adhesive, wherein the silicon-containing end-capping agent is introduced before, during, or after the reaction of the silicone resin and the silicone polymer, Among them:
After the polysiloxane resin and the polysiloxane polymer have undergone a condensation reaction to form a pressure-sensitive adhesive, the silicon-containing blocking agent reacts with the pressure-sensitive adhesive; or the silicon-containing blocking agent is on the spot Reacts with this silicone resin and silicone polymer.

According to some embodiments of the present invention, a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality includes a pressure-sensitive adhesive and a content providing acrylate or methacrylate functionality Condensation reaction product of silicon capping agent. That is, the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality is basically a capped with a silicon-containing capping agent that provides acrylate or methacrylate functionality Or endblocked) pressure-sensitive adhesive, wherein the pressure-sensitive adhesive contains a condensation reaction product of polysiloxane resin and polysiloxane polymer. Preferably, the silicone resin reacts in an amount of 30 to 80 parts by weight to form a pressure-sensitive adhesive, and the silicone polymer reacts in an amount of from 20 to 70 parts by weight to form a pressure-sensitive adhesive. Both of these parts by weight are based on 100 parts by weight of the pressure-sensitive adhesive. Although not required, the pressure-sensitive adhesive may contain a catalyst amount of a condensation catalyst. A wide variety of silicone resins and silicone polymers are suitable for forming pressure-sensitive adhesives.

According to some embodiments of the present invention, the polysiloxane acrylic pressure-sensitive adhesive is the following reaction product:
(a) A silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality, which contains the following condensation reaction product:
(a1) Silicone resin,
(a2) polysiloxane polymer, and
(a3) providing an acrylate or methacrylate functional silicon-containing blocking agent, wherein the silicon-containing blocking agent has the general formula XYR ' _b SiZ _3-b , wherein
X is a monovalent group of the general formula AE-,
Where E is -O- or -NH-, and A is acryl or methacryl,
Y is a divalent alkylene group having from 1 to 6 carbon atoms,
R 'is methyl or phenyl,
Z is a monovalent hydrolyzable organic group or halogen, and
b is 0 or 1;
Wherein the silicone resin and the silicone polymer react to form a pressure-sensitive adhesive, wherein the silicon-containing end-capping agent is introduced before, during, or after the reaction of the silicone resin and the silicone polymer, Among them:
After the polysiloxane resin and the polysiloxane polymer have undergone a condensation reaction to form a pressure-sensitive adhesive, the silicon-containing blocking agent reacts with the pressure-sensitive adhesive; or the silicon-containing blocking agent is on the spot Reacts with this silicone resin and silicone polymer.
(b) ethylenically unsaturated monomer; and
(c) Starter.

The polysiloxane-acrylic hybrid composition used in the present invention can be described by being prepared by a method including the following steps:
(i) Provide a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality, which contains the following condensation reaction product:
Polysiloxane resin,
Polysiloxane polymer, and a silicon-containing blocking agent that provides the acrylate or methacrylate functionality, wherein the silicon-containing blocking agent has the general formula XYR ' _b SiZ _3-b , where
X is a monovalent group of the general formula AE-,
Where E is -O- or -NH-, and A is acryl or methacryl,
Y is a divalent alkylene group having from 1 to 6 carbon atoms,
R 'is methyl or phenyl,
Z is a monovalent hydrolyzable organic group or halogen, and
b is 0 or 1;
Wherein the silicone resin and the silicone polymer react to form a pressure-sensitive adhesive, wherein the silicon-containing end-capping agent is introduced before, during, or after the reaction of the silicone resin and the silicone polymer, Among them:
After the polysiloxane resin and the polysiloxane polymer have undergone a condensation reaction to form a pressure-sensitive adhesive, the silicon-containing blocking agent reacts with the pressure-sensitive adhesive; or the silicon-containing blocking agent is on the spot React with the polysiloxane resin and polysiloxane polymer;
(ii) In the presence of an initiator, optionally at a temperature from 50 ° C to 100 ° C, or from 65 ° C to 90 ° C, polymerize the ethylenically unsaturated monomer and the step (i) containing acrylate or methyl ester A silicone-based pressure-sensitive adhesive composition based on acrylate functionality to form a silicone-acrylic hybrid composition.

During the polymerization of the ethylenically unsaturated monomer and the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality, the ratio of polysiloxane to acrylic can be controlled and optimized as needed. The ratio of polysiloxane to acrylic can be controlled by various mechanisms during and during this method. An illustrative example of this mechanism is the addition of ethylenically unsaturated monomers (or monomers) in a rate-controlled manner to a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality . In some applications, it may be desirable to have a polysiloxane-based subclass or all polysiloxane content exceeding the acrylate-based subclass or all acrylic content. In other applications, the opposite may be desired. Irrespective of the final application, as described above, it is generally preferred that the content of the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality is preferably in the polysiloxane-acrylic hybrid composition From about 5 to about 95 parts by weight, more preferably from about 25 to about 75 parts by weight, and still more preferably from about 40 to about 60 parts by weight, based on 100 parts by weight of the polysiloxane acrylic mixed composition Copies.

According to an embodiment of the present invention, the polysiloxane acrylic hybrid composition used in the present invention can be described by being prepared by a method including the following steps:
(i) Provide a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality, which contains the following condensation reaction product:
Polysiloxane resin,
Silicone polymer, and a silicon-containing end-capping agent that provides acrylate or methacrylate functionality, wherein the silicon-containing end-capping agent has the general formula XYR ' _b SiZ _3-b , where
X is a monovalent group of the general formula AE-,
Where E is -O- or -NH-, and A is acryl or methacryl,
Y is a divalent alkylene group having from 1 to 6 carbon atoms,
R 'is methyl or phenyl,
Z is a monovalent hydrolyzable organic group or halogen, and
b is 0 or 1;
Wherein the silicone resin and the silicone polymer react to form a pressure-sensitive adhesive, wherein the silicon-containing end-capping agent is introduced before, during, or after the reaction of the silicone resin and the silicone polymer, Among them:
After the polysiloxane resin and the polysiloxane polymer have undergone a condensation reaction to form a pressure-sensitive adhesive, the silicon-containing blocking agent reacts with the pressure-sensitive adhesive; or the silicon-containing blocking agent is on the spot Reacts with this silicone resin and silicone polymer.
(ii) The ethylenically unsaturated monomer and the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality of step (i) in the first solvent in the presence of an initiator Polymerization at a temperature of 50 ° C to 100 ° C to form a polysilicic acid acrylic hybrid composition;
(iii) remove the first solvent; and
(iv) Adding a second solvent to form a polysiloxane acrylic hybrid composition, wherein the phase arrangement of the polysiloxane acrylic hybrid composition is selectively controlled by selecting the second solvent.

The polysiloxane acrylic PSA composition used in the present invention can be described by being prepared by a method including the following steps:
(i) Provide a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality, which contains the following condensation reaction product:
Polysiloxane resin,
Silicone polymer, and a silicon-containing end-capping agent that provides acrylate or methacrylate functionality, wherein the silicon-containing end-capping agent has the general formula XYR ' _b SiZ _3-b , where
X is a monovalent group of the general formula AE-,
Where E is -O- or -NH-, and A is acryl or methacryl,
Y is a divalent alkylene group having from 1 to 6 carbon atoms,
R 'is methyl or phenyl,
Z is a monovalent hydrolyzable organic group or halogen, and
b is 0 or 1;
Wherein the silicone resin and the silicone polymer react to form a pressure-sensitive adhesive, wherein the silicon-containing end-capping agent is introduced before, during, or after the reaction of the silicone resin and the silicone polymer, Among them:
After the polysiloxane resin and the polysiloxane polymer have undergone a condensation reaction to form a pressure-sensitive adhesive, the silicon-containing blocking agent reacts with the pressure-sensitive adhesive; or the silicon-containing blocking agent is on the spot Reacts with this silicone resin and silicone polymer.
(ii) The ethylenically unsaturated monomer and the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality of step (i) in the first solvent in the presence of an initiator Polymerization at a temperature of 50 ° C to 100 ° C to form a polysilicic acid acrylic hybrid composition;
(iii) adding a processing solvent, wherein the processing solvent has a boiling point higher than that of the first solvent, and
(iv) applying heat at a temperature from 70 ° C to 150 ° C to selectively remove most of the first solvent;
(v) remove processing solvents; and
(vi) Adding a second solvent to form a polysiloxane acrylic hybrid composition, wherein the phase arrangement of the polysiloxane acrylic hybrid composition is selectively controlled by selecting the second solvent.

The polysiloxane resin according to the preceding paragraph may contain a copolymer comprising a triorganosiloxy unit of formula R ^X ₃ SiO _1/2 and a tetrafunctional siloxy unit of formula SiO _4/2 , triorganosilicon The ratio of units to each tetrafunctional siloxy unit is from 0.1 to 0.9, preferably about 0.6 to 0.9. Preferably, each R ^X independently represents a monovalent hydrocarbon group having from 1 to 6 carbon atoms, a vinyl group, a hydroxyl group or a phenyl group.

The polysiloxane polymer according to the preceding paragraph may contain at least one polydiorganosiloxane and is preferably end-capped or end-blocked with a functional group selected from the group consisting of: hydroxy, alkane Oxygen, hydride, vinyl, or mixtures thereof. The diorgano substituent can be selected from the group consisting of: dimethyl, methylvinyl, methylphenyl, diphenyl, methylethyl, (3,3,3-trifluoropropyl) Methyl and its mixtures. Preferably, the diorganic substituent contains only methyl groups. The molecular weight of the polydiorganosiloxane generally ranges from about 50,000 to about 1,000,000, preferably, from about 80,000 to about 300,000. Preferably, the polydiorganosiloxane comprises AR ^X SiO units terminated with TR ^X ASiO _1/2 units for termination, wherein the poly-diorganosiloxane has a value of from about 100 at 25 ° C. With a viscosity of centipoise to about 30,000,000 centipoise, each A group is independently selected from R ^X or a halogenated hydrocarbon group having from 1 to 6 carbon atoms, and each T group is independently selected from the group consisting of: R ^X , OH, H or OR ^Y , and each R ^{Y is} independently an alkyl group having from 1 to 4 carbon atoms.

For an example of a form using a preferred silicone resin and a preferred silicone polymer, a type of pressure-sensitive adhesive is manufactured by:
Mixing (i) from 30 to 80 parts by weight of at least one resin copolymer containing silicon-based hydroxyl groups and consisting essentially of R ^X ₃ SiO _1/2 units and SiO _4/2 units, R ^X ₃ SiO ₁ The molar ratio of _{/ 2} units to each SiO _4/2 unit is 0.6 to 0.9, (ii) at least one of between about 20 and about 70 parts by weight includes end capping with TR ^X ASiO _1/2 units AR ^X SiO unit polydiorganosiloxane, wherein the polydiorganosiloxane has a viscosity of from about 100 centipoise to about 30,000,000 centipoise at 25 ° C and each R ^X is selected from the group consisting of Monovalent organic groups of the group: hydrocarbon groups from 1 to 6 (inclusive) carbon atoms, each A group is independently selected from R ^X or a halogenated hydrocarbon group having from 1 to 6 (inclusive) carbon atoms, each The T group is independently selected from the group consisting of: R ^X , OH, H or OR ^Y , and each R ^{Y is} independently an alkyl group of from 1 to 4 (inclusive) carbon atoms; a sufficient amount of ( iii) At least one silicon-containing capping agent (also referred to as capping agent throughout) as described below and capable of providing a silanol content (or concentration in the range of 5,000 to 15,000, more often 8,000 to 13,000, ppm ), And when not provided (ii) At the time, if necessary, in addition to the catalyst amount of (iv) mild silanol condensation catalyst, and when necessary, an effective amount of (v) organic solvent, which ) Is inert to reduce the viscosity of the mixture of (i), (ii), (iii), and (iv), and condenses the mixture of (i), (ii), (iii), and (iv) at least until substantial The amount of silicon-containing capping agent or agent reacts with the silicon-bonded hydroxyl groups and T groups of (i) and (ii). The additional organosilicon capping agent can be used in combination with the silicon-containing capping agent or agent (iii) of the present invention.

The silicon-containing capping agent according to the preceding paragraph may be selected from the group of acrylate functional silane, acrylate functional silazane, acrylate functional disilazane, acrylate functional disilaxane, Methacrylate functional silane, methacrylate functional silazane, methacrylate functional disilazane, methacrylate functional disilaxane, and combinations thereof, and may also have the general formula XYR ' _b SiZ _3-b description, where X is a monovalent group of the general formula AE-, where E is -O- or -NH-, and A is acryl or methacryl, Y is from 1 to A divalent alkylene group of 6 carbon atoms, R ′ is a methyl group or a phenyl group, Z is a monovalent hydrolyzable organic group or halogen, and b is 0, 1, or 2. Preferably, the monovalent hydrolyzable organic group has the general formula R "0-, where R" is alkylene. Preferably, the specific end-capping agent is selected from the group consisting of: 3-methacryloxypropyl dimethyl chlorosilane, 3-methacryl oxypropyl dichlorosilane, 3-methyl Acryloyl propyl propyltrichlorosilane, 3-methacryl propyl propyl dimethyl methoxy silane, 3-methacryl propyl propyl methyl dimethoxy silane, 3-methyl Acrylic Acryloyloxypropyl Trimethoxysilane, 3-Methacrylic Acyloxypropyl Dimethylethoxysilane, 3-Methacrylic Acyloxypropyl Methyldiethoxysilane, 3- Methacryloyloxypropyltriethoxysilane, (methacryloyloxymethyl) dimethylmethoxysilane, (methacryloyloxymethyl) methyldimethoxysilane, (Methacryloyloxymethyl) trimethoxysilane, (methacryloyloxymethyl) dimethylethoxysilane, (methacryloyloxymethyl) methyldiethoxysilane , Methacryloxymethyltriethoxysilane, methacryloxy-propyltriisopropoxysilane, 3-methacryloxypropyldimethylsilazane, 3- Acryloyloxy-propyl dimethyl chlorosilane, 3-acryloyl Propylpropyldichlorosilane, 3-propenyloxypropyl-trichlorosilane, 3-propenyloxypropyl dimethylmethoxysilane, 3-propenyloxy-propylmethyldimethyl Oxysilane, 3-propenyloxypropyltrimethoxysilane, 3-propenyloxypropyl-dimethylsilazane, and combinations thereof.

The ethylenically unsaturated monomer according to the preceding paragraph may be any monomer having at least one carbon-carbon double bond. Preferably, the ethylenically unsaturated monomer according to the preceding paragraph may be a compound selected from the group consisting of aliphatic acrylate, aliphatic methacrylate, cycloaliphatic acrylate, cycloaliphatic methyl Acrylic esters, and combinations thereof. It should be understood that each of the compounds: aliphatic acrylate, aliphatic methacrylate, cycloaliphatic acrylate, and cycloaliphatic methacrylate includes an alkyl group. The alkyl group of these compounds may include up to 20 carbon atoms. The aliphatic acrylate selected as one of the ethylenically unsaturated monomers is selected from the group consisting of methyl acrylate, ethyl acrylate, propyl acrylate, n-butyl acrylate, isobutyl acrylate, acrylic acid Tertiary butyl ester, hexyl acrylate, 2-ethylhexyl acrylate, isooctyl acrylate, isononyl acrylate, isoamyl acrylate, tridecyl acrylate, stearyl acrylate, lauryl acrylate, and mixtures thereof. The aliphatic methacrylate selected as one of the ethylenically unsaturated monomers is selected from the group consisting of: methyl methacrylate, ethyl methacrylate, propyl methacrylate, methacrylic acid N-butyl ester, isobutyl methacrylate, tertiary butyl methacrylate, hexyl methacrylate, 2-ethylhexyl methacrylate, isooctyl methacrylate, isononyl methacrylate, methylmethacrylate Isoamyl acrylate, tridecyl methacrylate, stearyl methacrylate, lauryl methacrylate, and mixtures thereof. The cycloaliphatic acrylate which can be selected as one of the ethylenically unsaturated monomers is cyclohexyl acrylate, and the cycloaliphatic methacrylate which can be selected as one of the ethylenically unsaturated monomers is methacrylic rings Hexyl ester.

It should be understood that the ethylenically unsaturated monomers that can be used in the preparation of polysiloxane-acrylic hybrid pressure-sensitive adhesives can be more than one ethylenically unsaturated monomer. That is, the combination of ethylenically unsaturated monomers can be polymerized together with a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality and an initiator, and more specifically, copolymerized. According to an embodiment of the present invention, the polysiloxane acrylic pressure-sensitive adhesive is prepared by using at least two different ethylenically unsaturated monomers, preferably selected from 2-ethylhexyl acrylate For the group with methyl acrylate, the ratio of 50% 2-ethylhexyl acrylate and 50% methyl acrylate or 60% 2-ethylhexyl acrylate and 40% methyl acrylate Acrylic monomer.

The initiator according to the preceding paragraph may be any suitable for initiating the polymerization of a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality and an ethylenically unsaturated monomer to form a polysilicoxyacrylic system Mixed material. For example, free radical initiators selected from the group of peroxides, azo compounds, redox initiators, and their photoinitiators can be used.

Other suitable silicone resins, silicone polymers, silicon-containing capping agents, ethylenically unsaturated monomers, and initiators that can be used according to the preceding paragraphs are detailed in WO 2007/145996, EP 2 599 847 A1 and WO 2016/130408.

According to an embodiment of the present invention, the polysiloxane-acrylic hybrid polymer comprises a reaction product of a polysiloxane polymer, a polysiloxane resin, and an acrylic polymer, wherein the acrylic polymer is covalently self-crosslinked And covalently bonded to silicone polymer and / or silicone resin.

According to some other embodiment of the present invention, the polysiloxane-acrylic hybrid polymer comprises the reaction product of polysiloxane polymer, polysiloxane resin and acrylic polymer, wherein the polysiloxane resin contains triorganosilicon Oxygen unit R ₃ SiO _1/2 , where R is an organic group, and tetrafunctional siloxy unit SiO _4/2 , the molar ratio of R ₃ SiO _1/2 unit to each SiO _4/2 is from 0.1 To 0.9.

The acrylic polymer may include at least one alkoxysilyl functional monomer, polysiloxane-containing monomer, halosilyl functional monomer, or alkoxyhalosilyl functional monomer. Preferably, the acrylic polymer is prepared from an alkoxysilyl functional monomer selected from the group consisting of: trialkoxysilyl (meth) acrylate, dioxane (meth) acrylate Oxyalkylsilyl esters, and mixtures thereof, or contain blocked alkoxysilyl functional groups. The alkoxysilyl functional group is preferably selected from the group consisting of trimethoxysilyl, dimethoxymethylsilyl, triethoxysilyl, diethoxymethyl Silicone and its mixture.

The acrylic polymer can also be prepared from a mixture comprising polysiloxane-containing monomers, preferably from a mixture comprising polydimethylsiloxane mono (meth) acrylate.

The amount of the silicon-based functional monomer is usually from 0.2 to 20% by weight of the acrylic polymer, more preferably the amount of the silicon-based functional monomer is from about 1.5 to about 5% by weight of the acrylic polymer.

The amount of the polysiloxane-containing monomer is usually from 1.5 to 50% by weight of the acrylic polymer, more preferably the amount of the polysiloxane-containing monomer is from 5 to 15% by weight of the acrylic polymer .

Alternatively, the acrylic polymer includes a block or graft copolymer of acrylic and polysiloxane. An example of a polysiloxane block copolymer is a polydimethylsiloxane-acrylic block copolymer. The preferred amount of the siloxane block is 10 to 50% by weight of the entire block polymer.

The acrylic polymer contains alkyl (meth) acrylate monomers. The preferred alkyl (meth) acrylates that can be used can have up to about 18 carbon atoms in the alkyl group, and preferably have from 1 to about 12 carbon atoms in the alkyl group. Preferred low glass transition temperature (Tg) alkyl acrylates having a homopolymer Tg of less than about 0 ° C have from about 4 to about 10 carbon atoms in the alkyl group, including butyl acrylate, pentyl acrylate, hexyl acrylate , 2-ethylhexyl acrylate, octyl acrylate, isooctyl acrylate, isodecyl acrylate, isomers thereof, and combinations thereof. Particularly preferred are butyl acrylate, 2-ethylhexyl acrylate and isooctyl acrylate. The acrylic polymer component may further include (meth) acrylate monomers having high Tg, such as methyl acrylate, ethyl acrylate, methyl methacrylate, and isobutyl methacrylate.

The acrylic polymer component may further include polyisobutylene groups to improve the cold flow properties of the resulting adhesive.

The acrylic polymer component may include a nitrogen-containing polar monomer. Examples include N-vinylpyrrolidone, N-vinylcaprolactam, N-tertiary octylacrylamide, dimethylacrylamide, diacetone acrylamide, N-tertiary butylacrylamide Amine, N-isopropylacrylamide, cyanoethyl acrylate, N-vinylacetamide and N-vinylformamide.

The acrylic polymer component may include one or more hydroxyl-containing monomers, such as 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, hydroxypropyl acrylate, and / or hydroxypropyl methacrylate.

If necessary, the acrylic polymer component may include a carboxylic acid-containing monomer. Useful carboxylic acids preferably contain from about 3 to about 6 carbon atoms, especially including acrylic acid, methacrylic acid, itaconic acid, β-carboxyethyl acrylate, and the like. Acrylic is particularly preferred.

Other useful and well-known comonomers include vinyl acetate, styrene, cyclohexyl acrylate, alkyl di (meth) acrylate, glycidyl methacrylate and allyl glycidyl ether, and macromonomers, For example, poly (styryl) methacrylate.

One of the acrylic polymer components that can be used in the practice of the present invention is to contain from about 90 to about 99.5% by weight of butyl acrylate and from about 0.5 to about 10% by weight of dimethoxymethylsilyl methacrylate Of acrylic polymers.

According to an embodiment of the present invention, the polysiloxane-acrylic hybrid polymer can be formed by a) reacting the polysiloxane polymer and the polysiloxane resin to form the resulting product, b) making the product of a) and containing The reactive functional acrylic polymer is prepared by reaction, in which the components are reacted in an organic solvent.

According to an embodiment of the present invention, the polysiloxane-acrylic hybrid polymer can be formed by a) reacting the polysiloxane resin with an acrylic polymer containing reactive functionalities, b) a) The resulting product is prepared by reacting with a polysiloxane polymer, wherein these components are reacted in an organic solvent.

According to an embodiment of the present invention, the polysiloxane-acrylic hybrid polymer can be formed by a) reacting the polysiloxane polymer with an acrylic polymer containing reactive functionalities, b) a) The resulting product is prepared by reacting with silicone resin, wherein these components are reacted in an organic solvent.

Other suitable acrylic polymers, silicone resins, and other suitable acrylic polymers that can be used in chemical reactions with polysiloxane polymers, polysiloxane resins, and acrylic polymers to provide polysiloxane-acrylic hybrid polymers according to the preceding paragraph The polysiloxane polymer is described in detail in WO2010 / 124187.

According to some embodiments of the present invention, the polysiloxane-based acrylic hybrid polymer used in TTS is blended with one or more non-mixed polymers, preferably the polysiloxane-based acrylic hybrid polymer is combined with one or A variety of non-hybrid pressure-sensitive adhesives (such as pressure-sensitive adhesives based on polysiloxane or acrylate) are blended.

Non-hybrid polymer

According to an embodiment of the present invention, the TTS includes one or more non-hybrid polymers (for example, non-hybrid pressure-sensitive adhesives) in addition to the polysiloxane-based acrylic hybrid polymer. Non-hybrid polymers (eg, non-hybrid pressure-sensitive adhesives) are polymers that do not include hybrid species (eg, polymer-based pressure-sensitive adhesives). Non-mixed polymers based on polysiloxane, acrylate, polyisobutylene, or styrene-isoprene-styrene block copolymers (eg, non-mixed pressure-sensitive adhesives) are preferred.

Non-hybrid polymers (eg, non-hybrid pressure-sensitive adhesives) can be included in the active agent-containing layer structure and / or in the adhesive cover layer.

Non-mixed pressure-sensitive adhesives are usually supplied and used in solvents such as n-heptane and ethyl acetate. The solid content of pressure-sensitive adhesives is usually between 30% and 80%.

Suitable non-hybrid polymers according to the present invention are commercially available such as brand names BIO-PSAs (polysiloxane-based pressure sensitive adhesives), Oppanol ^TM (polyisobutylene), JSR-SIS (styrene-isoprene (Ene-styrene copolymer) or Duro-Tak ^™ (acrylic polymer).

Polysiloxane-based polymers may also be referred to as polysiloxane-based polymers or polysiloxane polymers, or polysiloxanes. Polysiloxane-based pressure-sensitive adhesives can also be called polysiloxane-based pressure-sensitive adhesives, or polysiloxane-based pressure-sensitive adhesives. These silicone-based pressure-sensitive adhesives provide proper adhesion and fast adhesion to various skin types (including wet skin), proper adhesion and adhesive quality, long-term adhesion to the skin, and high flexibility , Permeability to moisture, and compatibility with many active substances and film substrates. It is possible to provide them with sufficient amine resistance and therefore enhanced stability in the presence of amines. These pressure-sensitive adhesives are based on the concept of resin-in-polymer, in which polydimethylsiloxane and silicate resin (also called silicon Stone resin) by condensation reaction to prepare polysiloxane-based pressure-sensitive adhesives, wherein for amine stability, residual silanol functionality is additionally capped with trimethylsiloxy. The silanol-terminated polydimethylsiloxane content contributes to the viscoelastic properties of the viscous component and affects the wettability and ductility properties of the adhesive. The resin acts as an adhesive and reinforcing agent, and participates in the elastic component. The correct balance between the silanol-terminated polydimethylsiloxane and the resin provides the correct bonding properties.

In view of the above, polysiloxane polymers, and especially polysiloxane-based pressure-sensitive adhesives, are usually obtained by polycondensation of silanol-terminated polydimethylsiloxane and silicate resins. Amine-compatible polysiloxane polymers can be obtained by reacting polysiloxane polymers with trimethylsilyl groups (such as hexamethyldisilazane) in order to reduce the silanol content of the polymer. As a result, the residual silanol functionality is at least partially, preferably largely or completely capped with trimethylcarbonyl.

As indicated above, the adhesiveness of at least one polysiloxane polymer can be changed by the resin-to-polymer ratio, that is, the ratio of silanol-terminated polydimethylsiloxane to silicate resin. It is preferably in the range from 70:30 to 50:50, preferably from 65:35 to 55:45. The tackiness will increase as the amount of polymer relative to the resin increases. The high adhesive polysiloxane polymer preferably has a resin-to-polymer ratio of 55:45, and the medium adhesive polysiloxane polymer preferably has a resin-to-polymer ratio of 60:40. The low-adhesive polysiloxane polymer preferably has a resin-to-polymer ratio of 65:35. The high adhesive polysiloxane polymer preferably has a complex viscosity of 5 × 10 ⁶ poise at 0.01 rad / s and 30 ° C, and the medium adhesive polysiloxane polymer preferably has 0.01 rad / s and 30 It has a complex viscosity of 5 × 10 ⁷ poises at ℃, and the low adhesive polysiloxane polymer preferably has a complex viscosity of 5 × 10 ⁸ poises at 0.01 rad / s and 30 ° C. High adhesive amine-compatible polysiloxane polymer preferably has a complex viscosity of 5 × 10 ⁶ poise at 0.01 rad / s and 30 ° C, and medium adhesive amine-compatible polysiloxane polymer is preferred It has a complex viscosity of 5 × 10 ⁸ poise at 0.01 rad / s and 30 ° C, and a low-viscosity amine compatible polysiloxane polymer preferably has 5 × 10 at 0.01 rad / s and 30 ° C The complex viscosity of ⁹ poises.

Examples of commercially available polysiloxane-based PSA compositions include standard BIO-PSA series (7-4400, 7-4500, and 7-4600 series), amine-compatible (blocked) BIO-PSA series (7-4100, 7-4200 and 7-4300 series), which are manufactured by Dow Corning and are usually supplied in n-heptane or ethyl acetate, and Soft Skin Adhesive Series (7-9800), which are manufactured by Dow Corning and are usually free of solvents Form supply. For example, BIO-PSA 7-4201 is characterized by a solution viscosity of 450 mPa s at 25 ° C and about 70% solids content in heptane, and a complex viscosity of 1 × at 0.01 rad / s and 30 ° C 10 ⁸ moorings. BIO-PSA 7-4301 has a solution viscosity of 500 mPa s at 25 ° C and about 70% solids content in heptane, and a complex viscosity of 5 × 10 ⁶ poise at 0.01 rad / s and 30 ° C.

Silicone polymers, especially silicone-based pressure-sensitive adhesives, are supplied and used in solvents such as n-heptane, ethyl acetate or other volatile silicone fluids. The solid content of the polysiloxane polymer in the solvent is generally between 60 and 80 %%, preferably between 70 and 80% or between 60 and 70%. The skilled person understands that the solid content can be changed by adding an appropriate amount of solvent.

Silicone polymers, especially pressure-sensitive adhesives based on silicones, which are available for example from Dow Corning, can be obtained according to the following scheme:

These silicone polymers are also known as standard silicone adhesives and are available from Dow Corning, for example, under the trade name BIO-PSA 7-4401, BIO-PSA-7-4501, or BIO-PSA 7-4601 , Which is provided in the solvent n-heptane (indicated by the code "01"), or under the trade names BIO-PSA 7-4402, BIO-PSA 7-4502, and BIO 7-4602, which are in the solvent ethyl acetate (with Code "02" means provided in). Typical solids content in solvents ranges from 60 to 75%. Code "44" indicates a resin-to-polymer ratio of 65:35, resulting in low adhesion, code "45" indicates a resin-to-polymer ratio of 60:40, resulting in medium adhesion, code " 46 "means a 55:45 resin-to-polymer ratio, resulting in high tackiness.

Amine-compatible polysiloxane polymers, especially amine-compatible polysiloxane-based pressure-sensitive adhesives, which are available for example from Dow Corning, can be obtained according to the following scheme:

Such amine-compatible polysiloxane polymers are available from Dow Corning, for example, under the trade names BIO-PSA 7-4101, BIO-PSA-7-4201, or BIO-PSA 7-4301, which are Alkanes (indicated by the code "01"), or under the trade names BIO-PSA 7-4102, BIO-PSA 7-4202, and BIO 7-4302, which are in the solvent ethyl acetate (indicated by the code "02") Available in. Typical solids content in solvents ranges from 60 to 75%. Code "41" indicates a resin-to-polymer ratio of 65:35, resulting in low adhesion, code "42" indicates a resin-to-polymer ratio of 60:40, resulting in medium adhesion, code " 43 "means a 55:45 resin-to-polymer ratio, resulting in high tackiness.

The preferred silicone-based pressure-sensitive adhesives according to the invention are characterized by having a solids content of greater than about 150 mPa s or from about 200 mPa s to about 200 mPa s at 25 ° C and about 60% solids content in n-heptane The solution viscosity of 700 mPa s is preferably measured at 50 RPM using a Brookfield RVT viscometer equipped with a No. 5 rotor. These characteristics may also have a complex viscosity of less than about 1 × 10 ⁹ poise or from about 1 × 10 ⁵ to about 9 × 10 ⁸ poise at 0.01 rad / s and 30 ° C.

Suitable polyisobutylenes according to the invention are available under the trade name Oppanol®. A combination of high molecular weight polyisobutylene (B100 / B80) and low molecular weight polyisobutylene (B10, B11, B12, B13) can be used. The appropriate ratio of low molecular weight polyisobutylene to high molecular weight polyisobutylene is in the range from 100: 1 to 1: 100, preferably from 95: 5 to 40:60, more preferably from 90:10 to 80:20. A preferred example of a polyisobutylene combination is B10 / B100 at a ratio of 85/15. Oppanol® B100 has a viscosity average molecular weight M _v of 1,110,000, a weight average molecular weight M _{w of} 1,550,000, and an average molecular weight distribution M _w / M _{n of} 2.9. Oppanol® B10 has a viscosity average molecular weight M _{v of} 40,000, a weight average molecular weight M _{w of} 53,000, and an average molecular weight distribution M _w / M _{n of} 3.2. In some embodiments, polybutene can be added to polyisobutene. The solid content of polyisobutylene in the solvent is generally between 30 and 50%, preferably between 35 and 40%. The skilled person knows that the solid content can be changed by adding an appropriate amount of solvent.

Acrylate-based pressure-sensitive adhesives can also be referred to as acrylate-based pressure-sensitive adhesives, or acrylate pressure-sensitive adhesives. The acrylate-based pressure-sensitive adhesive may have a solid content preferably between 30% and 60%. Such acrylate-based pressure-sensitive adhesives may or may not contain functional groups, such as hydroxyl groups, carboxylic acid groups, neutralized carboxylic acid groups, and mixtures thereof. Therefore, the term "functional group" particularly refers to hydroxyl- and carboxylic acid groups and deprotonated carboxylic acid groups.

Corresponding commercial products are available from Henkel under the designation Duro Tak®, for example. The acrylate-based pressure-sensitive adhesives are based on monomers selected from one or more of the following: acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyl Ethyl acrylate, methacrylate, methyl methacrylate, tertiary octyl acrylamide and vinyl acetate, and ethyl acetate, heptane, n-heptane, hexane, methanol, Provided in ethanol, isopropanol, 2,4-pentanedione, toluene or xylene or mixtures thereof.

Specific acrylate-based pressure-sensitive adhesives can be obtained from:
-Duro-Tak ^TM 387-2287 or Duro-Tak ^TM 87-2287 (based on copolymers of vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate , Provided as a solution in ethyl acetate, without crosslinking agent),
- Duro-Tak ^TM 387-2516 or Duro-Tak ^TM 87-2516 (based on vinyl acetate, 2-ethylhexyl - methacrylate, 2-hydroxyethyl - methacrylate and glycidyl acrylate - methacrylate copolymers of , Provided in a solution of ethyl acetate, ethanol, n-heptane and methanol, with a titanium cross-linking agent),
-Duro‑Tak ^TM 387-2051 or Duro-Tak ^TM 87-2051 (based on a copolymer of acrylic acid, butyl acrylate, 2-ethylhexyl acrylate and vinyl acetate in ethyl acetate and heptane provide),
-Duro-Tak ^TM 387-2353 or Duro-Tak ^TM 87-2353 (based on a copolymer of acrylic acid, 2-ethylhexyl acrylate, glycidyl methacrylate and methacrylate in ethyl acetate and hexane Solution provided),
-Duro-Tak ^TM 87-4098 (based on a copolymer of 2-ethylhexyl-acrylate and vinyl acetate, supplied as a solution in ethyl acetate).

Additional polymers can also be added to enhance adhesion and / or adhesion.

Certain polymers particularly reduce cold flow and are therefore particularly suitable as additional polymers. The polymer matrix can show cold flow because these polymer compositions, although very viscous, usually exhibit very slow flow capacity. Therefore, during storage, the matrix can flow to some extent on the edge of the backing layer. This is a problem of storage stability and can be prevented by adding certain polymers. Basic acrylate polymers (eg Eudragit® E100) can be used, for example, to reduce cold flow. Therefore, in certain embodiments, the matrix layer composition additionally comprises a basic polymer, especially an amine functional acrylate, such as, for example, Eudragit® E100. Eudragit® E100 is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate having a ratio of 2: 1: 1. The monomers are randomly distributed along the copolymer chain. According to the SEC method, the weight average molar mass (Mw) of Eudragit® E100 is about 47,000 g / mol. In addition, polymers such as Plastoid B, acrylic polymers such as Eudragits, chitosan, cellulose and its derivatives, and polystyrene can be used to increase the dryness of the binder (eg, matrix layer).

Other additives

The TTS according to the invention, especially the guanfacine-containing layer, may further comprise at least one additive or excipient. Particularly preferred additives according to the present invention include dispersants, penetration enhancers, and co-solvents. Details in this regard are provided above. However, the TTS according to the invention, especially the guanfacine-containing layer, may also include other additives or excipients.

Generally, the additives or excipients are preferably selected from the group consisting of: dispersants, cosolvents, penetration enhancers, film forming agents, softeners / plasticizers, adhesives, skin care substances, pH adjustment Agents, preservatives, stabilizers, and fillers. The content of these additives in the guanfacine-containing layer may be from 0.001% to 15% by weight based on the total weight of the guanfacine-containing layer, for example from 0.5 to 10% by weight or from 1 to 10% by weight Or from 0.01 to 6% by weight, and the amount by weight described herein refers to a single additive.

It should be noted that the formulation components in pharmaceutical formulations are classified according to their physicochemical and physiological properties and according to their functions. This means in particular that a substance or compound belonging to one category does not exclude another category belonging to components of the formulation. For example, a polymer may be a film-forming agent, but also an adhesive. Some substances may for example be typical softeners, but at the same time act as penetration enhancers. The technician can determine the type or type of the formulation component to which a substance or compound belongs based on his general knowledge. Details on excipients and additives are provided below, however, such details should not be interpreted as exclusive. Other substances not explicitly listed in this description can also be used in accordance with the invention, and substances and / or compounds specifically listed as a component of the formulation do not exclude use as another formulation in the sense of the invention物 组合 物 Object composition.

In one embodiment, the guanfacine-containing layer includes a dispersing agent as defined above, preferably the dispersing agent is selected from the group consisting of: esters of fatty acids and polyols, fatty alcohols, with 300 to 400 Polyethylene glycol and polyethylene glycol alkyl ether with a number average molecular weight. As explained above, the dispersant is preferably a polyethylene glycol C ₈ -C ₂₀ -alkyl ether having 2 to 10 EO units (in particular polyoxyethylene (4) lauryl ether). Alternatively or additionally, polysiloxane polyether can be used as a dispersant. The dispersant helps to uniformly disperse guanfacine in the layer containing guanfacine, especially in the matrix layer of guanfacine, thereby improving the release properties of TTS.

In one embodiment, the guanfacine-containing layer contains a co-solvent. The cosolvent preferably improves the dispersion of guanfacine in the layer containing guanfacine and stabilizes the layer containing guanfacine. In addition, co-solvents can positively affect adhesion. Preferred co-solvents include, for example, glycerides, polyglycerides, propylene glycol esters and polyoxyethylene esters of medium-chain and / or long-chain fatty acids, such as glycerol monolinoleate, medium-chain glycerides and medium-chain triglycerides Nonionic co-solvent made by reacting castor oil with ethylene oxide, and any mixtures thereof that may additionally contain fatty acids or fatty alcohols; cellulose and methyl cellulose and their derivatives such as hydroxypropyl fiber And hydroxypropyl methylcellulose acetate succinate, various cyclodextrins and their derivatives; known as poloxamer (poloxamer) with two polyoxyethylene side hydrophilic chains flanked by polyoxypropylene center hydrophobic Chain nonionic triblock copolymer; water-soluble derivatives of vitamin E; pharmaceutical grade or agglomerated spherical isomaltose; graft copolymerization based on polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam Substances, also abbreviated as PVAc-PVCap-PEG and called Soluplus®; vinylpyrrolidone-vinyl acetate copolymers such as Kollidon® VA64; purified grade of naturally derived castor oil, polyethylene glycol 400, polyoxyethylene Sorbitan monooleate ( Such as polysorbate 80) or propylene glycol; diethylene glycol monoethyl ether; glucono-delta-lactone; corn and potato starch; and soluble polyvinylpyrrolidone mentioned below and It is also any of insoluble / crosslinked polyvinylpyrrolidone (such as crospovidone).

However, the penetration enhancers described below can also serve as co-solvents. In addition, the following film-forming agent can also act as a cosolvent, and vice versa.

In one embodiment, the guanfacine-containing layer contains a penetration enhancer. Preferences in this regard are provided above. Permeation enhancers are substances that affect the barrier properties of the stratum corneum in the sense of increasing the permeability of the active agent. Some examples of penetration enhancers are polyols such as dipropylene glycol, propylene glycol, and polyethylene glycol; oils such as olive oil, squalene, and lanolin; fatty ethers such as cetyl ether and oleyl ether; fatty acid esters such as myristic acid Isopropyl ester; urea and urea derivatives such as allantoin; polar solvents such as dimethyl decyl phosphoxide, methyl cetyl sulfoxide, aurylamine, dodecyl Pyrrolidone, isosorbide, dimethyl acetal compound, dimethyl sulfoxide, decylmethyl sulfoxide, and dimethylformamide; salicylic acid; amino acid; benzyl nicotinate; and Higher molecular weight aliphatic surfactants such as lauryl sulfate. Other agents include oleic acid and linoleic acid, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate and tocopheryl linoleate, propyl oleate, and isopropyl palmitate. If the guanfacine-containing layer contains a penetration enhancer, the penetration enhancer is preferably selected from the group consisting of: diethylene glycol monoethyl ether (transcutol), oleic acid, levulinic acid , Trioctylglycerol / tridecylglycerol, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, triacetin, dimethyl propionate Base urea, and oleyl alcohol, and preferably oleyl alcohol.

In one embodiment, the guanfacine-containing layer further includes a film-forming agent. It should be understood that the aforementioned co-solvents, such as Soluplus®, can also act as film-forming agents and control adhesion. Suitable examples of other film-forming agents include polyvinylpyrrolidone, vinyl acetate / vinylpyrrolidone copolymer and cellulose derivatives, preferably polyvinylpyrrolidone, more preferably soluble polyvinylpyrrolidone Pyridone.

If the guanfacine-containing layer is required to have self-adhesive properties and one or more polymers are selected (providing / not providing sufficient self-adhesiveness), an adhesive is added. Preferred adhesives include Miglyol, which is a liquid wax ester based on long-chain unsaturated even-numbered fatty acids and plant-derived long-chain unsaturated even-numbered fatty alcohols, and polyethylene glycol. In particular, the adhesive may be selected from polyvinylpyrrolidone (due to its water-absorbing ability, capable of maintaining the adhesive properties of the matrix layer and therefore can be regarded as a broad-based adhesive), triglyceride, polyethylene glycol, diglyceride Propylene glycol, resins, resin esters, terpenes and their derivatives, ethylene vinyl acetate adhesives, dimethyl polysiloxane and polybutene, preferably polyvinylpyrrolidone, and more preferably soluble poly Vinylpyrrolidone. Preferably, the adhesive may be selected from polyvinylpyrrolidone, triglyceride, dipropylene glycol, resin, resin ester, terpenes and their derivatives, ethylene vinyl acetate adhesive, dimethyl polysilicone The oxane and polybutene are preferably polyvinylpyrrolidone, and more preferably soluble polyvinylpyrrolidone.

The term "soluble polyvinylpyrrolidone" refers to polyvinylpyrrolidone, also known as povidone, which is in at least ethanol, preferably also in water, diethylene glycol, methanol, n-propylene Solubility in alcohol, 2 propanol, n-butanol, chloroform, methylene chloride, 2-pyrrolidone, macrogol 400, 1,2 propanediol, 1,4 butanediol, glycerin, triethanolamine, propionic acid and acetic acid exceeds 10%. Examples of commercially available polyvinylpyrrolidone include Kollidon® 12 PF, Kollidon® 17 PF, Kollidon® 25, Kollidon® 30, and Kollidon® 90 F supplied by BASF, or Povidone K90F. The different grades of Kollidon® are defined according to the K-value reflecting the average molecular weight of the polyvinylpyrrolidone grade. Kollidon® 12 PF features a K-value range of 10.2 to 13.8, which corresponds to a nominal K-value of 12. Kollidon® 17 PF features a K-value range of 15.3 to 18.4, which corresponds to a nominal K-value of 17. Kollidon® 25 features a K-value range of 22.5 to 27.0, corresponding to a nominal K-value of 25, and Kollidon® 30 features a K-value range of 27.0 to 32.4, corresponding to a nominal K-value of 30. Kollidon® 90 F features a K-value range of 81.0 to 97.2, corresponding to a nominal K-value of 90. The preferred Kollidon® grades are Kollidon® 12 PF, Kollidon® 30 and Kollidon® 90 F. Within the meaning of the present invention, the term "K-value" refers to a value calculated from the relative viscosity of polyvinylpyrrolidone in water according to the USP monographs of the European Pharmacopoeia (Ph. Eur.) And "Providone".

In one embodiment, the guanfacine-containing layer further includes a softener / plasticizer. Exemplary softeners / plasticizers include linear or branched saturated or unsaturated alcohols having 6 to 20 carbon atoms, triglycerides, and polyethylene glycol.

In one embodiment, the guanfacine-containing layer further includes a stabilizer. Stabilizers include tocopherol and its ester derivatives and ascorbic acid and its ester derivatives. Other stabilizers include sodium metabisulfite, ascorbyl esters of fatty acids such as ascorbyl palmitate, ascorbic acid, butylated hydroxytoluene, tocopherol, tocopheryl acetate and tocopheryl linoleate.

In one embodiment, the guanfacine-containing layer further contains a pH adjusting agent. Suitable pH adjusting agents include weak acids and bases, including amine derivatives, inorganic base derivatives, and polymers with basic or acidic functionality.

In one embodiment, the guanfacine-containing layer further contains a preservative. Suitable preservatives include parabens, formaldehyde releasing agents, isothiazolinone, phenoxyethanol, and organic acids such as benzoic acid, sorbic acid, levulinic acid and anisic acid.

In one embodiment, the guanfacine-containing layer further contains skin care substances. These substances can be used to avoid or reduce skin irritation, as measured by a skin reaction score. Suitable skin care substances include sterol compounds such as cholesterol, dextran-panthenol, alpha-bisabolol, and anti-histamine.

In one embodiment, the guanfacine-containing layer further contains a filler. Fillers such as silicone, titanium dioxide, and zinc oxide can be used in conjunction with polymers to influence certain physical parameters, such as adhesion and bond strength, in the desired manner.

Release characteristics

The TTS according to the present invention is designed for percutaneous administration of guanfacine to systemic circulation for a predetermined extended period of time, preferably at least 24 hours, more preferably at least 72 hours, especially about 84 hours.

In one embodiment, the TTS according to the present invention is delivered percutaneously in a stable state to provide guanfacine from 1 to 20 ng / ml, preferably from 1 to 15 ng / ml, more preferably from 1 to 10 ng / ml Plasma concentration.

Preferably, the therapeutically effective plasma concentration of guanfacine is provided within less than 8 hours, preferably less than 6 hours, and more preferably less than 4 hours after TTS is applied to the skin. In addition, the therapeutically effective plasma concentration is preferably maintained throughout the administration period of at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours.

In one embodiment, the TTS according to the present invention provides AUC _{0-24h of} 10 to 600 ng * h / ml, preferably 20 to 400 ng * h / ml. In another embodiment, the TTS according to the present invention provides AUC _{0-72h of} 30 to 1800 ng * h / ml, preferably 60 to 1200 ng * h / ml. In another embodiment, the TTS according to the present invention provides AUC _{0-84h of} 35 to 2100 ng * h / ml, preferably 70 to 1400 ng * h / ml. It should be understood that the AUC value preferably refers to the AUC value obtained in a steady state.

In one embodiment, the TTS according to the invention provides a ratio of C _max to C ₈₄ of less than 3.5. In another embodiment, the TTS according to the present invention provides a ratio of C _max to C ₇₂ of less than 3.0. In another embodiment, the TTS according to the present invention provides a ratio of C _max to C ₂₄ of less than 2.0. This ratio represents a flat plasma curve, which is advantageous in terms of continuous treatment of the patient.

In one embodiment, the TTS according to the present invention provides the following skin penetration rates of guanfacine as measured by human skin divided by a dermatome in a Franz diffuser:
From 0.01 µg / (cm ² * h) to 8 µg / (cm ² * h) in the first 24 hours,
From 24 hours to 72 hours, it is 0.05 µg / (cm ² * h) to 10 µg / (cm ² * h).

In one embodiment, the TTS according to the present invention provides 0.01 mg / cm² to 0.7 mg / cm², preferably 0.05 mg over a 72-hour period, as measured in human skin divided by a percutaneous knife in the Franz diffusion tank / cm² to 0.6 mg / cm², more preferably 0.15 to 0.3 mg / cm ² guanfacine skin penetration.

In view of the above, the present invention also relates to a transdermal therapeutic system for transdermal administration of guanfacine in one aspect, which includes a layer structure containing guanfacine,
Wherein the transdermal therapeutic system provides one or more pharmacokinetic parameters selected from the group consisting of:
AUC _0-24 from 10 to 600 (ng / mL) h,
AUC _0-72 from 30 to 1800 (ng / mL) h,
AUC _0-84 from 35 to 2100 (ng / mL) h,
The ratio of C _max to C ₂₄ less than 2.0,
The ratio of C _max to C ₇₂ less than 3.0, and the ratio of C _max to C ₈₄ less than 3.5.

In a preferred embodiment, the present invention relates to a transdermal therapeutic system for percutaneous administration of guanfacine, which includes a layer structure containing guanfacine,
Wherein the transdermal therapeutic system provides one or more pharmacokinetic parameters selected from the group consisting of:
AUC _0-24 from 20 to 400 (ng / mL) h,
AUC _0-72 from 60 to 1200 (ng / mL) h,
AUC _0-84 from 70 to 1400 (ng / mL) h,
The ratio of C _max to C ₂₄ less than 1.5,
The ratio of C _max to C ₇₂ less than 2.5, and the ratio of C _max to C ₈₄ less than 3.0.

In a particularly preferred embodiment, the present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine, which includes a layer structure containing guanfacine, wherein the transdermal therapeutic system is provided by transdermal delivery. AUC _0-84 from 70 to 1400 (ng / mL) h.

Treatment / medical use

In one embodiment of the present invention, the TTS according to the present invention is suitable for use in a method for treating human patients (preferably human patients aged from 6 to 17 years old). In particular, the TTS according to the present invention is suitable for the treatment of hypertension or attention deficit hyperactivity disorder (ADHD) in human patients (preferably human patients aged from 6 to 17 years) and / or used as a stimulant In the method of adjuvant therapy.

In a preferred embodiment related to the above medical use, the TTS system is applied to the patient's skin for at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours.

In one embodiment, the present invention relates to a method for treating a human patient (preferably a human patient from 6 to 17 years of age), which is a transdermal treatment as defined in any one of items 1 to 37 The system is applied to the patient's skin. In particular, the present invention relates to the treatment of high blood pressure or attention deficit hyperactivity disorder (ADHD) in human patients (preferably human patients from 6 to 17 years of age). Apply to patient's skin.

In one preferred embodiment of the above treatment method, the transdermal therapeutic system is applied to the patient's skin for at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours.

In view of the above, the present invention in one aspect relates to a transdermal therapeutic system containing guanfacine, which is used to treat human patients by transdermal administration of guanfacine (preferably from 6 to 17 years old) Human patient), wherein the transdermal therapeutic system is applied to the patient's skin for at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours. In a preferred embodiment, the transdermal therapeutic system is used in the treatment of hypertension or attention deficit hyperactivity disorder (ADHD) in human patients and / or as an adjunct therapy for stimulating drug therapy. In a more preferred embodiment, the transdermal therapeutic system is a transdermal therapeutic system according to the present invention, particularly a transdermal therapeutic system that provides one or more pharmacokinetic parameters selected from the group consisting of :
AUC _0-24 from 10 to 600 (ng / mL) h,
AUC _0-72 from 30 to 1800 (ng / mL) h,
AUC _0-84 from 35 to 2100 (ng / mL) h,
The ratio of C _max to C ₂₄ less than 2.0,
The ratio of C _max to C ₇₂ less than 3.0, and the ratio of C _max to C ₈₄ less than 3.5;
And it is preferably selected from the group consisting of:
AUC _0-24 from 20 to 400 (ng / mL) h,
AUC _0-72 from 60 to 1200 (ng / mL) h,
AUC _0-84 from 70 to 1400 (ng / mL) h,
The ratio of C _max to C ₂₄ less than 1.5,
The ratio of C _max to C ₇₂ less than 2.5, and the ratio of C _max to C ₈₄ less than 3.0.

In another aspect, the present invention relates to guanfacine, which is a transdermal therapeutic system for the transdermal administration of guanfacine for the treatment of human patients (preferably human patients from 6 to 17 years old) In the method, wherein the transdermal therapeutic system is applied to the patient's skin for at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours. In a preferred embodiment, guanfacine is used in the treatment of high blood pressure or attention deficit hyperactivity disorder (ADHD) in human patients and / or as an adjunct therapy for stimulating drug therapy. In a more preferred embodiment, the transdermal therapeutic system is a transdermal therapeutic system according to the present invention, particularly a transdermal therapeutic system that provides one or more of the pharmacokinetic parameters selected from the group consisting of :
AUC _0-24 from 10 to 600 (ng / mL) h,
AUC _0-72 from 30 to 1800 (ng / mL) h,
AUC _0-84 from 35 to 2100 (ng / mL) h,
The ratio of C _max to C ₂₄ less than 2.0,
The ratio of C _max to C ₇₂ less than 3.0, and the ratio of C _max to C ₈₄ less than 3.5;
And it is preferably selected from the group consisting of:
AUC _0-24 from 20 to 400 (ng / mL) h,
AUC _0-72 from 60 to 1200 (ng / mL) h,
AUC _0-84 from 70 to 1400 (ng / mL) h,
The ratio of C _max to C ₂₄ less than 1.5,
The ratio of C _max to C ₇₂ less than 2.5, and the ratio of C _max to C ₈₄ less than 3.0.

In another aspect, the invention relates to a method of treating human patients (preferably human patients aged from 6 to 17 years) by transdermal administration of guanfacine, wherein the transdermal therapeutic system is applied to the patient The skin experienced at least 24 hours, preferably at least 72 hours, more preferably about 84 hours. In a preferred embodiment, the method is used to treat high blood pressure or attention deficit hyperactivity disorder (ADHD) in human patients and / or as an adjunct therapy for stimulating medication. In a more preferred embodiment, the transdermal therapeutic system is a transdermal therapeutic system according to the present invention, particularly a transdermal therapeutic system that provides one or more pharmacokinetic parameters selected from the group consisting of:
AUC _0-24 from 10 to 600 (ng / mL) h,
AUC _0-72 from 30 to 1800 (ng / mL) h,
AUC _0-84 from 35 to 2100 (ng / mL) h,
The ratio of C _max to C ₂₄ less than 2.0,
The ratio of C _max to C ₇₂ less than 3.0, and the ratio of C _max to C ₈₄ less than 3.5;
And preferably selected from the group consisting of:
AUC _0-24 from 20 to 400 (ng / mL) h,
AUC _0-72 from 60 to 1200 (ng / mL) h,
AUC _0-84 from 70 to 1400 (ng / mL) h,
The ratio of C _max to C ₂₄ less than 1.5,
The ratio of C _max to C ₇₂ less than 2.5, and the ratio of C _max to C ₈₄ less than 3.0.

Regarding the above therapeutic uses and methods, the TTS according to the present invention is preferably applied to at least one body surface selected from the upper outer arm, upper chest, upper back, or side of the chest on the subject body to undergo a defined administration interval.

The preferred application time of the TTS according to the present invention is at least 24 hours (1 day), preferably at least 72 hours (3 days), and more preferably about 84 hours (3.5 days). After this time, the TTS can be removed and new TTS can be applied at will to allow 24/7 treatment.

Manufacturing method

The invention further relates to a method of manufacturing a guanfacine-containing layer (preferably a guanfacine-containing matrix layer) used in a transdermal therapeutic system.

According to the present invention, the method of manufacturing the guanfacine-containing layer used in the transdermal therapeutic system according to the present invention includes the following steps:
1) Combine at least the following components:
i) guanfacine; and
ii) at least one polysiloxane acrylic hybrid polymer,
To obtain a coating composition;
2) Apply the coating composition on the backing layer or release liner to obtain the coated coating composition; and
3) The coated coating composition is dried to form a guanfacine-containing layer.

In step 1) of the above manufacturing method, guanfacine is preferably dispersed in the polymer to obtain a uniform coating composition.

It should be understood that in step 1), other ingredients may be added, preferably at least one non-mixed polymer and / or at least one additive as defined above.

Preferably, a solvent is added in step 1) of the method, and / or because one or more polymers are provided in the form of a solution, a solvent is present. The solvent is preferably selected from alcohol solvents, especially methanol, ethanol, isopropanol, and mixtures thereof, and from non-alcohol solvents, especially ethyl acetate, hexane, heptane, petroleum ether, toluene, and mixtures thereof, It is more preferably selected from non-alcoholic solvents, and most preferably ethyl acetate or n-heptane. In a particularly preferred embodiment, the solvent is ethyl acetate.

In a preferred embodiment, the polysiloxane-based hybrid polymer is provided as a solution, wherein the solvent is ethyl acetate or n-heptane, preferably ethyl acetate.

In a preferred embodiment, the polysiloxane-based acrylic hybrid polymer has a solid content of 40 to 60% by weight.

In step 2) of the method, the coating composition is applied to the backing layer or release liner. As a result, a coated coating composition, that is, a coating composition coated on the backing layer or the release liner is obtained.

After forming the guanfacine-containing layer in step 3), the method may therefore further include a step in which a release liner or backing layer is applied to the other side of the guanfacine-containing layer.

In step 3) of the above manufacturing method, drying is preferably performed at a temperature of from 20 to 90 ° C, more preferably from 40 to 70 ° C. Drying preferably requires at least 1 hour, preferably at least 8 hours, such as 1 day.

Examples

The present invention will now be described more fully with reference to the accompanying examples. However, it should be understood that the following description is only an example and should not be construed as limiting the invention in any way. The numerical values provided in the examples regarding the amounts of ingredients or area weights in the composition may be slightly changed due to manufacturing variability.

Example 1A-C
Paint composition

The formulations of the guanfacine-containing coating composition of Examples 1a-c are summarized in Tables 1.1a and 1.1b below. The% -value refers to the amount in% by weight (Amt).

Preparation of paint composition

The drug substance was dispersed in the solvent ethyl acetate and sonicated for 5 min. Then add the adhesive. These two steps can also be performed in reverse order. The mixture was homogenized with a dissolving stirrer at 2000 rpm for 10 minutes.

Coating of coating composition

The resulting guanfacine-containing coating composition is coated on a polyethylene terephthalate film (Scotchpak 9755, which can be Used as a release liner), and dried at about 50 ℃ for about 10 minutes. Depending on the target area weight, the corresponding applicator gap is between 150-350 µm.

The thickness of the coating is selected so that after removing the solution, an area weight of about 87 (Example 1a), 160 (Example 1b), and 142 (Example 1c) g / m ² guanfacine-containing layer is obtained. The dried film was then laminated with a backing layer (PET 15 µm tsp) to provide a self-adhesive layer structure containing guanfacine.

Preparation of TTS (for all examples)

Next, each system (TTS) was stamped from the self-adhesive layer structure containing guanfacine obtained as described above. Next, the TTS is sealed in a pouch of direct packaging material.

Measurement of skin penetration

The permeation of TTS prepared according to Examples 1a-c was determined by experiments conducted with a 10.0 mL Franz diffusion cell according to OECD guidelines (April 13, 2004 edition). Split-thickness Goettinger minipig skin (female) was used. A skin knife is used to prepare skin with a thickness of 800 µm and a complete epidermis is used for all TTS. From the TTS, die cuts with a release area of 1.179 cm ^{2 were} punched. Measure the penetration of guanfacine in the receptor medium (phosphate buffer solution pH 5.5 with 0.1% sodium azide as antibacterial agent) of Franz diffusion tank at a temperature of 32 ± 1 ℃ and calculate the corresponding cumulative penetration .

The results are shown in Table 1.2 and Figure 1.

Example 2A-D
Paint composition

The formulations of the guanfacine-containing coating composition of Examples 2a-d are summarized in Tables 2.1a and 2.1b below. The% -value refers to the amount in% by weight.

Preparation of paint composition

The drug substance and enhancer used were dispersed in the solvent ethyl acetate and sonicated for about 10 min. Then add the adhesive. These two steps can also be performed in reverse order. The mixture was homogenized at 2000 rpm for 2-4 minutes using a dissolving stirrer. The material was further homogenized at 1500 rpm for 30 min.
In the case of compositions 2a and 2b, Soluplus was added after the mixture was homogenized at 2000 rpm for about 2 minutes. The material was stirred at 2000 rpm for another 2 min, and further homogenized at 1500 rpm for 30 min.

Coating of coating composition

For coating methods, see Examples 1a-c. The coating thickness produced 100 (Example 2a), 158 (Example 2b), 97 (Example 2c) and 155 (Example 2d) g / m ² area weight of the guanfacine-containing layer. The dried film was laminated with a backing layer (PET 15 µm tsp) to provide a self-adhesive layer structure containing guanfacine.

Preparation of TTS

See Example 1.

Measurement of skin penetration

The permeation of TTS prepared according to Examples 2a-d was determined by experiments conducted with a 10.0 mL Franz diffusion cell according to OECD guidelines (April 13, 2004 edition). Layered human skin from cosmetic surgery (eg, female abdomen, date of birth 1985) is used. Use a scalpel to prepare 500 µm thick skin and use it with a complete epidermis for all TTS. Die-cut with a release area of 1.191 cm ^{2 was} punched from the TTS. Measure the penetration of guanfacine in the receptor medium (phosphate buffer solution pH 5.5 with 0.1% sodium azide as antibacterial agent) of Franz diffusion tank at a temperature of 32 ± 1 ℃ and calculate the corresponding cumulative penetration .

The results are shown in Table 2.2 and Figure 2.

Example 3A-B

The formulations of the guanfacine-containing coating composition of Examples 3a-b are summarized in Table 3.1. The% -value refers to the amount in% by weight.

Preparation of the coating composition The drug substance and the reinforcing agent used are dispersed in the solvent ethyl acetate and treated with ultrasound for 5-10 min. Then add the adhesive. These two steps can also be performed in reverse order. The mixture was homogenized at 2000 rpm for 2-5 minutes with a dissolving stirrer. The material was further homogenized at 1500 rpm for 30 min.
In the case of composition 3a, Soluplus was added after the mixture was homogenized at 2000 rpm for about 5 minutes. The material was stirred at 2000 rpm for another 2 min, and further homogenized at 1500 rpm for 30 min.

Coating of coating composition

For coating methods, see Examples 1a-c. The coating thickness resulted in an area weight of 76 (Example 3a) and 97 (Example 3b) g / m ² guanfacine-containing layers. The dried film was laminated with a backing layer (PET 15 µm tsp) to provide a self-adhesive layer structure containing guanfacine.

Preparation of TTS

See Example 1.

Measurement of skin penetration

The penetration of TTS prepared according to Examples 3a-3b was determined as described in Examples 2a-d above. Die cuts with a release area of 1.188 cm ^{2 were} punched from TTS.

The results are shown in Table 3.2 and Figure 3.

Example 4A-G
Paint composition

The formulations of the guanfacine-containing coating compositions of Examples 4a-g are summarized in Tables 4.1a, 4.1b and 4.1c below. The% -value refers to the amount in% by weight.

Preparation of paint composition

The used drug substance and enhancer are dispersed in the solvent ethyl acetate and treated with ultrasound for 2-10 min. Then add the adhesive. These two steps can also be performed in reverse order. The mixture was homogenized with a dissolving stirrer (Example 4b, Example 4g turbo stirrer) at 1400-2000 rpm for about 10 minutes.
In the case of composition 4e, the used reinforcing agent was dispersed in the solvent ethyl acetate and treated with a magnetic stirrer at 60 ° C. for 10 min. The drug substance was added to the mixture and sonicated at 1400 rpm for about 3 min. Then add the binder and stir with a magnetic stirrer for about 5 min.

Coating of coating composition

For coating methods, see Examples 1a-c. Coating thickness results in 154 (Example 4a), 156 (Example 4b), 149 (Example 4c), 188 (Example 4d), 142 (Example 4e), 152 (Example 4f) and 154 (Example 4g) The area weight of the g / m ² guanfacine-containing layer. The dried film was laminated with a backing layer (PET 15 µm tsp) to provide a self-adhesive layer structure containing guanfacine.

Preparation of TTS

See Example 1.

Measurement of skin penetration

The penetration of TTS prepared according to Examples 4a-g was determined as described in Examples 2a-d above. Die-cut with a release area of 1.179 cm ^{2 was} punched from TTS.

The results are shown in Tables 4.2a and 4.2b and Figures 4a and 4b.

Example 5A-C
Paint composition

The formulations of the guanfacine-containing coating composition of Examples 5a-c are summarized in Tables 5.1a and 5.1b below. The% -value refers to the amount in% by weight.

Preparation of paint composition

The drug substance and enhancer used were dispersed in the solvent ethyl acetate and sonicated for about 10 min. Then add the adhesive. These two steps can also be performed in reverse order. The mixture was homogenized at 2000 rpm for about 2 minutes with a dissolving stirrer. Soluplus was added and the material was stirred at 2000 rpm for about 2 minutes, and further homogenized at 1500 rpm for at least 30 minutes.
In the case of composition 5c, Soluplus was added together with the binder and homogenized at 2000 rpm for about 2 min and further homogenized at 1500 rpm for at least 30 min.

Coating of coating composition

For coating methods, see Examples 1a-c. The coating thickness resulted in an area weight of about 100 (Example 5a), 106 (Example 5b), and 110 (Example 5c) g / m ² guanfacine-containing layers. The dried film was then laminated with a backing layer (PET 15 µm tsp) to provide a self-adhesive layer structure containing guanfacine.

Preparation of TTS

See Example 1.

Measurement of skin penetration

The penetration of TTS prepared according to Examples 5a-c was determined as described in Examples 2a-d above. Die-cut with a release area of 1.188 cm ^{2 was} punched from TTS.

The results are shown in Table 5.2 and Figure 5.

Example 6A-E
Paint composition

The formulations of the guanfacine-containing coating compositions of Examples 6a-e are summarized in Tables 6.1a and 6.1b below. The% -value refers to the amount in% by weight.

Preparation of paint composition

In the case of compositions 6a and 6b, the used drug substance and enhancer are dispersed and treated with ultrasound for 5-10 min. Next, the binder and ethyl acetate are added. These two steps can also be performed in reverse order. The mixture was homogenized at 1500 rpm for about 10 minutes with a dissolving stirrer.
In the case of compositions 6c and 6e, the used drug substance and enhancer are dispersed in the solvent ethyl acetate and treated with ultrasound for 5-10 min. Then add the adhesive. These two steps can also be performed in reverse order. The mixture is homogenized at 1500-2000 rpm for about 10 minutes using a turbo agitator (6c) or a dissolving agitator (6e).
In the case of composition 6d, the used drug substance was dispersed in the solvent ethyl acetate and treated with ultrasound for 5 min. Next, a binder was added and the mixture was stirred at 2000 rpm for about 5 min. The enhancer used was further added with stirring and the mixture was homogenized at 2000 rpm for about 15 min. Subsequently, the material was stirred at 500 rpm for about 60 min.

Coating of coating composition

For coating methods, see Examples 1a-c. The coating thickness produced 151 (Example 6a), 150 (Example 6b) g / m ² , 153 (Example 6c) g / m ² , 143 (Example 6d) g / m ² and 143 (Example 6e) Area weight of g / m ² layer containing guanfacine. The dried film was laminated with a backing layer (PET 15 µm tsp) to provide a self-adhesive layer structure containing guanfacine.

Preparation of TTS

See Example 1.

Measurement of skin penetration

The permeation of TTS prepared according to Examples 6a-e was determined by experiments conducted with a 10.0 mL Franz diffusion cell according to the OECD guidelines (April 13, 2004 edition). Use layered Goettinger minipig skin (female). A skin knife is used to prepare skin with a thickness of 800 µm and a complete epidermis is used for all TTS. From the TTS, die cuts with a release area of 1.179 cm ^{2 were} punched. Measure the penetration of guanfacine in the receptor medium (phosphate buffer solution pH 5.5 with 0.1% sodium azide as antibacterial agent) of Franz diffusion tank at a temperature of 32 ± 1 ℃ and calculate the corresponding cumulative penetration .

The results are shown in Tables 6.2a and 6.2b and Figure 6.

Example 7A-D
Paint composition

The formulations of the guanfacine-containing coating compositions of Examples 7a-d are summarized in Tables 7.1a and 7.1b of the following table. The% -value refers to the amount in% by weight.

Preparation of paint composition

The drug substance and enhancer used were dispersed in the solvent ethyl acetate and sonicated for about 5 min. Then add the adhesive. These two steps can also be performed in reverse order. The mixture was homogenized with a stirrer at 2000 rpm for 5 minutes. The material is stirred again at 1000-1500 rpm for about 10-15 minutes.

Coating of coating composition

For coating methods, see Examples 1a-c. The coating thickness produced an area weight of 74 (Example 7a), 101 (Example 7b), 95 (Example 7c), and 98 (Example 7d) g / m ² guanfacine-containing layers. The dried film was laminated with a backing layer (PET 15 µm tsp) to provide a self-adhesive layer structure containing guanfacine.

Preparation of TTS

See Example 1.

Measurement of skin penetration

The penetration of TTS prepared according to Examples 7a-d was determined as described in Examples 2a-d above. Die-cut with a release area of 1.188 cm ^{2 was} punched from TTS.

The results are shown in Tables 7.2a and 7.2b and Figure 7.

Example 8
Paint composition

The formulation of the guanfacine-containing coating composition of Example 8 is summarized in Table 8.1 below. The% -value refers to the amount in% by weight.

Preparation of paint composition

The drug substance and enhancer used were dispersed in the solvent ethyl acetate and sonicated for about 5 min. Next, the binder and ethyl acetate are added. The mixture was homogenized at 1500 rpm for about 10 minutes with a dissolving stirrer.

Coating of coating composition

For coating methods, see Examples 1a-c. The coating thickness results in an area weight of the guanfacine-containing layer of 143 g / m ² . The dried film was laminated with a backing layer (PET 15 µm tsp) to provide a self-adhesive layer structure containing guanfacine.

Preparation of TTS

See Example 1.

Measurement of skin penetration

The permeation amount of TTS prepared according to Example 8 was determined by an experiment conducted with a 10.0 mL Franz diffusion cell according to OECD guidelines (April 13, 2004 edition). Use layered Goettinger minipig skin (female). A skin knife is used to prepare skin with a thickness of 800 µm and a complete epidermis is used for all TTS. Die cuts with a release area of 1.188 cm ^{2 were} punched from the TTS. Measure the penetration of guanfacine in the receptor medium (phosphate buffer solution pH 5.5 with 0.1% sodium azide as antibacterial agent) of Franz diffusion tank at a temperature of 32 ± 1 ℃ and calculate the corresponding cumulative penetration .

The results are shown in Table 8.2 and Figure 8.

Example 9A-C

The formulations of the guanfacine-containing coating composition of Examples 9a-c are summarized in Table 9.1 below. The% -value refers to the amount in% by weight.

Preparation of the coating composition The drug substance and the reinforcing agent used are dispersed in the solvent ethyl acetate. Then add the adhesive. These two steps can also be performed in reverse order. The mixture was homogenized at 2000 rpm for 2-5 minutes with a dissolving stirrer. The material was stirred again at 1500 rpm for about 30 minutes.
In the case of composition 9b, Soluplus was added after the mixture was homogenized at 2000 rpm for 2 minutes. The material was stirred at 2000 rpm for about 2 minutes and further homogenized at 1500 rpm for about 30 minutes.

Coating of coating composition

For coating methods, see Examples 1a-c. The coating thickness produced an area weight of 104 (Example 9a), 95 (Example 9b) and 95 (Example 9c) g / m ² guanfacine-containing layers. The dried film was laminated with a backing layer (PET 15 µm tsp) to provide a self-adhesive layer structure containing guanfacine.

Preparation of TTS

See Example 1.

Measurement of skin penetration

The penetration of TTS prepared according to Examples 9a-c was determined as described in Examples 2a-d above. Die-cut with a release area of 1.188 cm ^{2 was} punched from TTS.

The results are shown in Table 9.2 and Figure 9.

Example 10
In vivo clinical research

In vivo clinical trials were conducted to study the relative bioavailability of guanfacine after transdermal administration of the TTS of the present invention (Examples 9b and 9c). The research is based on the moral principles derived from the Declaration of Helsinki.

Test design

A trial of a fixed treatment sequence with 4 treatments and 3 treatment periods was performed in a single center Phase I open label design in 12 healthy male and female subjects, with the purpose of comparing The TTS of the present invention (each having a size of 15 cm ² ) is administered transdermally or orally with 1 mg extended-release tablets (available from Shire's IntunivRetard®, 1 mg, once daily) over 84 h (3.5 days) Single-dose pharmacokinetics of guanfacine.

For each subject, the trial consisted of the following:
• During dynamic screening, where informed consent was obtained and subject qualifications were evaluated. Depending on the results of the screening, subjects are included in the trial.
• A treatment and observation period consisting of 3 consecutive treatment periods (a few days each).
• Follow up dynamically after the last treatment.

Choice of test group

Only subjects who met all inclusion criteria and no exclusion criteria were included in the treatment period. Evaluate the criteria at the time of screening and recheck on the first day of Phase 1.

Inclusion criteria

Subjects must meet all of the following criteria to be eligible to participate in the treatment period.
1. Subjects who can understand and follow instructions during the study.
2. Sign the informed consent.
3. Caucasian.
4. Age ≥18 and ≤55 years old.
5. Non-smokers.
6. General health is determined by medical and surgical history, physical examination, 12-lead electrocardiogram (ECG), vital signs and clinical laboratory tests.
7. According to the recognized body mass index (BMI) value, the body weight is within the normal range of 18.0 to 29.4 kg / m ² .
8. Normal blood pressure measured after resting for 5 minutes in supine position (systolic blood pressure (SBP) ≥90 ≤139 mmHg; diastolic blood pressure ≥ 55 ≤ 89 mmHg).
9. The pulse rate measured after resting in the supine position for 5 minutes is ≥50 and ≤99b / min.
10. ECG records have no clinically significant abnormalities.
11. There was no fever or infectious disease 7 days before the first administration.

Exclusion criteria

To ensure that the subjects are healthy and in a comparable state, the following exclusion criteria apply.

Lifestyle restrictions
1. Proof of excessive consumption of xanthine (more than 5 cups of coffee or equivalent per day).
2. Excessive drinking (habitually> 35 g of ethanol per day or weekly> 245 g).
3. Any history of alcohol or drug abuse.
4. Vegetarians.
5. Positive drug screening.
6. Positive alcohol breath test.
7. Consume foods or beverages containing xanthine and grapefruit juice or lime within 48 hours before the first dose.
8. Consume charcoal grilled food, broccoli, or Brussels sprouts within 72 hours before the first dose.

Prior medical treatment
9. Use any medication (self-medication or prescription medication) within 4 weeks before the first dose, except for hormonal contraception (or at least 10 times each elimination half-life, whichever is longer).

Medical and surgical history
10. Show any acute or chronic current physical illness.
11. Any medical allergies, asthma, urticaria or other severe allergies and a history of hay fever.
12. A history of allergy to any component of any dosage form studied.
13. Any history of chronic gastritis or gastric ulcer.
14. Any chronic or recurrent metabolism, kidney, liver, lung, gastrointestinal, nervous system (especially history of seizures), endocrine (especially diabetes), immunity, psychosis or cardiovascular disease, myopathy, skin disease and bleeding tendency Medical history.
15. Gilbert syndrome.
16. Any gastrointestinal discomfort within 7 days before the first dose.
17. Any scars, moles, tattoos, skin irritation, or excessive hair growth at the TTS application site.
18. In the past 12 months, any suicidal idea of type 2 to 5 in C-SSRS (Columbia Suicide Severity Rating Scale) (ie active suicidal idea, methodic active suicidal idea, intentional active suicidal idea but No specific plan, or active suicidal thoughts with plans and intentions).

Laboratory examination
19. Laboratory values outside the reference range are clinically relevant (for example, suggesting an unknown disease and requiring further clinical evaluation by the investigator), especially regarding aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamine transpeptidase (GGT).
20. Positive test for human immunodeficiency virus (HIV) antibody / p24 antigen.
21. Positive hepatitis B virus surface antigen (HBsAg) test.
22. Positive anti-hepatitis C virus antibody (anti-HCV) test.

other
23. Donate blood within 30 days before signing the informed consent.
24. The 30-day treatment period of participation in clinical research or the follow-up period of the previous clinical trial before signing the informed consent of this trial is blocked.
25. Women with fertility potential who do not use efficient birth control methods. An efficient method of birth control is defined as a method that results in a low failure rate (ie, less than 1% per year) when used consistently and correctly (eg, a combination of intrauterine device and condom). Female subjects are considered to have fertility potential unless by hysterectomy or bilateral fallopian tube ligation or menopause for 2 years.
26. Pregnant or lactating women.

Treatment during the study

The treatment administered during the study is summarized below.

Test product 1:
TTS containing guanfacine 9.0 mg (formulation according to Example 9c)
Content: 9 mg / 15 cm ²
Estimated daily release: about 1 mg
Administration route: Percutaneous treatment period: 3.5 days

Test product 2:
TTS containing guanfacine 18.0 mg (formulation according to Example 9b)
Content: 18 mg / 15 cm ²
Estimated daily release: about 1.5 mg
Administration route: Percutaneous treatment period: 3.5 days

Test product 3:
TTS with placebo (compound containing 50% by weight of SilAc 7-6102 and 50% by weight of SilAc 7-6302)
Content: 0 mg / 15 cm ²
Estimated daily release:-
Administration route: Percutaneous treatment period: 3.5 days

Activity control / reference (R):
Commercially available oral extended-release formulations (Intuniv® 1 mg)
Strength: 1 mg
Administration route: during oral treatment: single dose

Oral lozenge administration (control)

Lozenges are administered in a single dose in the morning.

Application of TTS

Apply TTS to the entire skin of the upper chest or upper back in the morning. If necessary, before application, trim the hair of the application area with scissors (unshaved). Subjects were instructed to verify that the skin was free of detergents, oils and fats before applying TTS. Place the TTS in the desired position and press with your fingers or palm for at least 30 seconds to fix the TTS on the skin surface. TTS was removed after 3.5 days (84 h). After removal, the TTS used was treated and stored in the refrigerator under nitrogen until further analysis.

Administration time of each subject

On the first day of treatment, no breakfast was served; subjects fasted overnight before the morning administration. A standardized lunch is given 4 hours after the morning administration and a dinner is given about 10 hours later. Ingestion of fluids is not allowed 1 hour before administration in the morning and evening until after 1 hour. If food does not interact with TTS, subjects receive standardized meals and beverages at the customary time within the internal days of the treatment period. During the internal days, subjects were only allowed to eat or drink food or beverages provided by the research unit.

Limitations and considerations

During the trial, the subjects were instructed to avoid all activities that might increase body temperature, namely physical exertion, sauna, and very hot environment. During the use of TTS, subjects were not allowed to perform any activity that might affect the adhesion of TTS, such as any activity that would increase sweating. For example, according to exclusion criteria, further restrictions on food and beverage intake.

Sample collection and plasma concentration determination

Blood samples used to determine the concentration of guanfacine in plasma were collected at designated time points after administration.

Adverse events (AE)

The investigators used non-leading questions to determine adverse events, which were spontaneously reported to the medical staff by the subjects, or were observed after administration of the dosage form during any measurement period on all study days and scored by the study doctor.

AE refers to treatment and the time point after treatment, ie, any AE that occurred before the first dose is counted as a baseline complaint / pre-treatment AE and is not included in the analysis below.

Results and analysis

All 12 subjects completed the study. The results of the study are shown in Table 10.a.

Geometric mean plasma concentration of guanfacine (n = 12)

The geometric mean value based on the plasma concentration of guanfacine in all 12 subjects was determined and shown in Figure 11 (guanfacine plasma concentration (ng / mL) vs. time (h)). AUC values were calculated from plasma concentrations and presented with C _max and t _max values in Table 10a.

Lower limit of quantification (LLOQ) = 0.05 ng / mL

The literature parameters of Intuniv lozenges are provided in Table 10b.

Residual amount of guanfacine in used TTS (n = 12)

The residual amount of guanfacine in the used TTS was determined by extracting from a sample of the TTS used with an appropriate solvent, and then using a verified HPLC method using a UV and photometric detector to determine the amount of guanfacine. The results are provided in Table 10c.

Adverse events (AE)

Table 10d reflects the number of adverse events reported in different categories.

Most AEs are related to IMP and only one event (neck pain) has nothing to do. None of the AEs observed were severe or severe. All incidents were resolved at the end of the study.

The most commonly observed AEs were fatigue (12 events in 5 subjects), dizziness (6 events in 4 subjects), and itching at the TTS application site (5 subjects 6 events).

N: the number of subjects in the designated treatment group; F: the number of adverse events;
n: number of subjects with at least one adverse event in this category;%: percentage of subjects with adverse events
R = reference (1 mg ER guanfacine tablet (single oral dose))
T1P = Test product 1 (transdermal therapeutic system, 9 mg / 15 cm²) plus placebo (15 cm ² )
T2 = Test product 2 (transdermal therapeutic system, 18 mg / 15 cm²)

Skin irritation

After removing TTS, the mild skin reaction was short-lived and subsided. In terms of the maximum combined skin response score, there was no difference between activity and placebo TTS.

in conclusion

The results of this exploratory study show that guanfacine can be administered via the transdermal route. However, the absorption after applying a patch with a size of 15 cm ² is significantly slower and occurs to a lesser extent than oral administration. The total exposure is about 30% to 50% of the exposure observed after oral administration and is not related to the concentration of guanfacine in TTS, but is consistent with the release of guanfacine calculated beyond the residual content in TTS. The safety of guanfacine after transdermal delivery is comparable to the oral administration in this study.

In conclusion, the results of this clinical study indicate that the required plasma concentration can be achieved by adjusting the patch size.

Comparative example 1

Comparative Example 1 (Comp.-Ex. 1) is a mixture of Oppanol B10 and Oppanol B100 with a 15/85 ratio and the main drug of guanfacine. The formulation of the coating composition containing guanfacine in Comparative Example 1 is summarized in Table 10.1 below. The% -value refers to the amount in% by weight.

Preparation of paint composition

The drug substance was dispersed in the solvent n-heptane and sonicated for 10 min. Next, the binder mixture is added. These two steps can also be performed in reverse order. The mixture was homogenized at 100-500 rpm for 30 minutes using a dissolving stirrer.

Coating of coating composition

For coating methods, see Examples 1a-c. The thickness of the coating resulted in an area weight of 91 (Comparative Example 1) g / m ² of the guanfacine-containing layer. The dried film was laminated with a backing layer (siliconized MN 19) to provide a self-adhesive layer structure containing guanfacine.

Preparation of TTS

See Example 1.

Measurement of skin penetration

The penetration of TTS prepared according to Comparative Example 1 was measured as described in Examples 2a-d above. Die-cut with a release area of 1.188 cm ^{2 was} punched from TTS.

The results are shown in Table 10.2 and Figure 5.

Comparative Example 2A-B
Paint composition

The formulations of the coating compositions containing guanfacine in Comparative Examples 2a-b are summarized in Table 11.1 below. The% -value refers to the amount in% by weight.

Preparation of paint composition

The drug substance was dispersed in the solvent ethyl acetate and sonicated for about 5 min. Then add the adhesive. These two steps can also be performed in reverse order. The mixture was homogenized at 500-800 rpm for about 10 minutes with a dissolving stirrer. In the case of Comparative Example 2a, the drug substance was directly dispersed in the adhesive. The mixture was stirred at 500 rpm for about 10 minutes.

Coating of coating composition

For coating methods, see Examples 1a-c. Regarding Comparative Example 2b, the coating composition was coated on a PET 100 µm film. The coating thickness resulted in an area weight of 49 (Comparative Example 2a) and 50 (Comparative Example 2b) g / m ² guanfacine-containing layer. The dried film was laminated with a backing layer (PET 15 µm tsp) to provide a self-adhesive layer structure containing guanfacine.

Preparation of TTS

See Example 1.

Measurement of skin penetration

The permeation of TTS prepared according to Comparative Examples 2a-b was determined by experiments conducted with a 10.0 mL Franz diffusion cell according to the OECD guidelines (April 13, 2004 edition). Use layered Goettinger minipig skin (female). A skin knife is used to prepare skin with a thickness of 800 µm and a complete epidermis is used for all TTS. Die-cuts with a release area of 1.165 cm ^{2 were} punched from the TTS. Measure the penetration of guanfacine in the receptor medium (phosphate buffer solution pH 5.5 with 0.1% sodium azide as antibacterial agent) of Franz diffusion tank at a temperature of 32 ± 1 ℃ and calculate the corresponding cumulative penetration .

The results are shown in Table 11.2 and Figure 10.

The present invention is particularly concerned with the following other items:
1. A transdermal therapeutic system for percutaneous administration of guanfacine, which includes a layer structure containing guanfacine, the layer structure containing guanfacine comprising
A) Backing layer; and
B) A layer containing guanfacine;
Wherein the transdermal therapeutic system includes at least one polysiloxane acrylic hybrid polymer.
2. The percutaneous treatment system according to item 1,
The guanidine-faxine-containing layer is a guanidine-faxine-containing matrix layer, which includes:
i) guanfacine; and
ii) At least one polysiloxane acrylic hybrid polymer.
3. The percutaneous treatment system according to any one of items 1 or 2,
The layer structure containing guanfacine is self-adhesive, and preferably does not include an additional skin contact layer.
4. The percutaneous treatment system according to any one of items 1 to 3,
Wherein the at least one polysiloxane acrylic hybrid polymer is a polysiloxane acrylic hybrid pressure sensitive adhesive.
5. The percutaneous treatment system according to any one of items 1 to 4,
The layer structure containing guanfacine contains a therapeutically effective amount of guanfacine.
6. The percutaneous treatment system according to any one of items 1 to 5,
The guanfacine in the guanfafaxin-containing layer structure exists in the form of free base, which is preferably dispersed in the guanfafaxin-containing layer.
7. The percutaneous treatment system according to any one of items 1 to 6,
The layer structure containing guanfacine contains guanfacine in an amount of from 1 to 100 mg / TTS, preferably from 8 to 72 mg / TTS.
8. The percutaneous treatment system according to any one of items 1 to 7,
Wherein, the guanidine-containing layer contains guanfacine, and the amount thereof is from 1 to 20%, more preferably from 3 to 16% by weight based on the total weight of the guanidine-containing layer.
9. The percutaneous treatment system according to any one of items 1 to 8,
Wherein the guanfafaxin-containing layer contains at least one polysilicoxyacrylic hybrid polymer in an amount of from 20 to 99%, preferably from 30 to 97%, based on the total weight of the guanfafacine-containing layer Best from 35 to 94% by weight,
It is preferred that the at least one polysiloxane acrylic hybrid polymer includes a polysiloxane phase and an acrylate phase in a weight ratio of from 60:40 to 40:60.
10. The transdermal therapeutic system according to any one of items 1 to 9, wherein the guanfacine-containing layer contains a first polysiloxane-based acrylic hybrid polymer in an amount of from 60 to 90% by weight, and Disiloxane-acrylic acid-based hybrid polymer, the amount of which is from 1 to 10% by weight, based on the total weight of the guanfacine-containing layer in each case,
It is preferred that the first polysiloxane acrylic hybrid polymer and the second polysiloxane acrylic hybrid polymer include a polysiloxane phase and an acrylate phase in a weight ratio of from 60:40 to 40:60.
11. The percutaneous treatment system according to any one of items 1 to 10,
Wherein the guanfacine-containing layer further comprises at least one non-hybrid polymer, preferably a pressure-sensitive adhesive non-hybrid polymer.
12. The percutaneous treatment system according to item 11,
The at least one non-hybrid polymer is selected from the group consisting of polysiloxane and acrylate.
13. The percutaneous treatment system according to any one of items 11 or 12,
The content of the at least one non-hybrid polymer is from 5 to 50%, preferably from 20 to 40% by weight based on the total weight of the guanfacine-containing layer.
14. The percutaneous treatment system according to any one of items 11 to 13,
The weight ratio of the at least one polysiloxane acrylic hybrid polymer to at least one non-hybrid polymer is from 10: 1 to 1: 2, preferably from 2: 1 to 1: 2.
15. The percutaneous treatment system according to any one of items 1 to 14,
Wherein the polysiloxane-acrylic hybrid polymer comprises the reaction product of polysiloxane, polysiloxane resin and acrylic polymer, wherein the acrylic polymer is covalently self-crosslinked and covalently bonded to the polysilicon Oxygen polymer and / or the polysiloxane resin.
16. The percutaneous treatment system according to any one of items 1 to 14,
Wherein the polysiloxane-based acrylic hybrid polymer is a polysiloxane-based acrylic hybrid pressure-sensitive adhesive obtained from the following:
(a) A silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality.
17. The percutaneous treatment system according to any one of items 1 to 14 or 16,
The polysiloxane-based acrylic hybrid polymer is a polysiloxane-based acrylic hybrid pressure-sensitive adhesive, which contains the following reaction products:
(a) Silicone-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality;
(b) ethylenically unsaturated monomer; and
(c) Starter.
18. The percutaneous treatment system according to any one of items 16 or 17,
The silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality includes the following condensation reaction products:
(a1) Silicone resin, and
(a2) polysiloxane polymer, and
(a3) Silicon-containing blocking agent containing acrylate or methacrylate functionality.
19. The percutaneous treatment system according to any one of items 16 to 18,
The silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality includes the following condensation reaction products:
(a1) Silicone resin, and
(a2) polysiloxane polymer, and
(a3) A silicon-containing blocking agent containing acrylate or methacrylate functionality, wherein the silicon-containing blocking agent has the general formula XYR ' _b SiZ _3-b , where X is a monovalent group of the general formula AE , Where E is -O- or -NH-, and A is acryloyl or methacryloyl, Y is a divalent alkylene group having from 1 to 6 carbon atoms, and R 'is methyl or phenyl , Z is a monovalent hydrolyzable organic group or halogen, and b is 0 or 1;
Wherein the silicone resin and the silicone polymer react to form a pressure-sensitive adhesive, wherein the silicon-containing end-capping agent is introduced before, during, or after the reaction of the silicone resin and the silicone polymer,
And after the polysiloxane resin and polysiloxane polymer have undergone a condensation reaction to form a pressure-sensitive adhesive, the silicon-containing blocking agent reacts with the pressure-sensitive adhesive, or the silicon-containing blocking agent The agent reacts with the silicone resin and silicone polymer on the spot.
20. The percutaneous treatment system according to any one of items 17 to 19,
Wherein the ethylenically unsaturated single system is selected from the group consisting of: aliphatic acrylate, aliphatic methacrylate, cycloaliphatic acrylate, cycloaliphatic methacrylate, and combinations thereof, these compounds Each has up to 20 carbon atoms in the alkyl group, and the ethylenically unsaturated monomer is preferably a combination of 2-ethylhexyl acrylate and methyl acrylate, particularly preferably from 40:60 to 70:30 ratio.
21. The percutaneous treatment system according to any one of items 17 to 20,
Among the following reaction products:
(a) Silicone-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality;
(b) ethylenically unsaturated monomer; and
(c) The initiator contains a continuous acrylic external phase and a discontinuous polysiloxane internal phase.
22. The percutaneous treatment system according to any one of items 1 to 21,
Wherein the guanfacine-containing layer further comprises at least one additive selected from the group consisting of: dispersant, penetration enhancer, and co-solvent, or at least two additives selected from the group consisting of: dispersion Agent, penetration enhancer, and co-solvent, preferably resulting in the presence of a combination of dispersant and penetration enhancer, or a combination of dispersant and co-solvent, or combination of penetration enhancer and co-solvent, or at least three selected from the group consisting of The group of additives: dispersant, penetration enhancer, and co-solvent, preferably resulting in a combination of dispersant, penetration enhancer, and co-solvent.
23. The transdermal therapeutic system according to item 22, wherein the dispersant is selected from the group consisting of: esters of fatty acids and polyols, fatty alcohols, polyethylene glycol having a number average molecular weight of 300 to 400, poly Glycol alkyl ether, and wherein the dispersant is preferably polyethylene glycol C ₈ -C ₂₀ -alkyl ether having 2 to 10 EO units.
24. The percutaneous treatment system according to item 22 or 23, wherein the penetration enhancer is selected from the group consisting of: diethylene glycol monoethyl ether (transcutol), oleic acid, levulinic acid, Trioctanoic acid / capric acid ester, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, triacetin, dimethyl propyl urea, And oleyl alcohol, and preferably oleyl alcohol.
25. The transdermal therapeutic system according to any one of items 22 to 24, wherein the co-solvent is selected from the group consisting of: a copolymer derived from an ester of acrylic acid and methacrylic acid, polyvinylpyrrolidone , Vinylpyrrolidone-vinyl acetate copolymer, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and preferably polyvinyl caprolactam-polyacetic acid Vinyl ester-polyethylene glycol graft copolymer.
26. The percutaneous treatment system according to any one of items 1 to 25,
The area weight of the guanfacine-containing layer ranges from 40 to 250 g / m ² , preferably from 50 to 180 g / m ² .
27. The percutaneous treatment system according to any one of items 23 to 26,
The content of the at least one additive is from 0.5 to 10% by weight or from 1 to 10% by weight based on the total weight of the guanfacine-containing layer.
28. The percutaneous treatment system according to any one of items 1 to 27,
Wherein the guanfacine loading range of the transdermal therapeutic system is from 0.2 to 2.4 mg / cm ² , preferably from 0.2 to 1.5 mg / cm ² ; and / or wherein the release area ranges from 1 to 100 cm ² , preferably from 2.5 to 50 cm ² .
29. The percutaneous treatment system according to any one of items 1 to 28,
Wherein the transdermal therapeutic system is delivered percutaneously in a stable state to provide an average plasma concentration of guanfacine from 1 to 20 ng / ml, preferably from 1 to 15 ng / ml.
30. The percutaneous treatment system according to any one of items 1 to 29,
It has an AUC _0-24h of about 10 to 600 ng * h / ml, preferably about 20 to 400 ng * h / ml.
31. The percutaneous treatment system according to any one of items 1 to 30,
It has an AUC _0-72h of about 30 to 1800 ng * h / ml, preferably about 60 to 1200 ng * h / ml.
32. The percutaneous treatment system according to any one of items 1 to 31,
It has an AUC _0-84h of about 35 to 2100 ng * h / ml, preferably about 70 to 1400 ng * h / ml.
33. The percutaneous treatment system according to any one of items 1 to 32,
Has a ratio of C _max to C ₈₄ less than 3.5.
34. The percutaneous treatment system according to any one of items 1 to 33,
Has a ratio of C _max to C ₇₂ less than 3.0.
35. The percutaneous treatment system according to any one of items 1 to 34,
Has a ratio of C _max to C ₂₄ less than 2.0.
36. The percutaneous treatment system according to any one of items 1 to 35,
As measured by human skin divided by a dermatome in the Franz diffuser, the following skin penetration rates of guanfacine are provided:
From 0.01 µg / (cm ² * h) to 8 µg / (cm ² * h) in the first 24 hours,
From 24 hours to 72 hours, it is 0.05 µg / (cm ² * h) to 10 µg / (cm ² * h).
37. The percutaneous treatment system according to any one of items 1 to 36,
As measured by human skin divided by a dermatome in the Franz diffusion tank, it provides 0.01 mg / cm² to 0.7 mg / cm², preferably 0.05 mg / cm² to 0.6 mg / cm², and more preferably 0.15 to 72 hours The skin penetration of guanfacine 0.3 mg / cm².
38. The transdermal therapeutic system according to any one of items 1 to 37, which is used in a method for treating human patients (preferably human patients aged from 6 to 17 years).
39. The transdermal therapeutic system according to any one of items 1 to 37, which is used to treat high blood pressure or attention deficit hyperactivity disorder in human patients (preferably human patients from 6 to 17 years old) ( ADHD) and / or as an adjunct therapy for stimulating drug therapy.
40. The transdermal therapeutic system according to any one of items 38 or 39, wherein the transdermal therapeutic system is applied to the patient's skin for at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours.
41. A method of treating a human patient (preferably a human patient between 6 and 17 years old) by applying a transdermal therapeutic system as defined in any one of items 1 to 37 to the patient's skin.
42. A method of treating high blood pressure or attention deficit hyperactivity disorder (ADHD) in a human patient (preferably a human patient between 6 and 17 years old), which is obtained by applying any one of items 1 to 37 The defined transdermal therapeutic system is applied to the patient's skin.
43. The method for treating a human patient according to any one of items 41 or 42, wherein the transdermal therapeutic system is applied to the patient's skin for at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours.
44. A transdermal therapeutic system for percutaneous administration of guanfacine, which includes a layer structure containing guanfacine,
Wherein the transdermal therapeutic system provides one or more pharmacokinetic parameters selected from the group consisting of:
AUC _0-24 from 10 to 600 (ng / mL) h,
AUC _0-72 from 30 to 1800 (ng / mL) h,
AUC _0-84 from 35 to 2100 (ng / mL) h,
The ratio of C _max to C ₂₄ less than 2.0,
The ratio of C _max to C ₇₂ less than 3.0, and the ratio of C _max to C ₈₄ less than 3.5.
45. The percutaneous treatment system according to item 44,
Wherein the transdermal therapeutic system provides one or more pharmacokinetic parameters selected from the group consisting of:
AUC _0-24 from 20 to 400 (ng / mL) h,
AUC _0-72 from 60 to 1200 (ng / mL) h,
AUC _0-84 from 70 to 1400 (ng / mL) h,
The ratio of C _max to C ₂₄ less than 1.5,
The ratio of C _max to C ₇₂ less than 2.5, and the ratio of C _max to C ₈₄ less than 3.0.
46. A transdermal therapeutic system comprising guanfacine for use in the percutaneous administration of guanfacine to treat human patients (preferably human patients aged 6 to 17 years), wherein the transdermal therapeutic system The system is applied to the patient's skin for at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours.
47. A transdermal therapeutic system containing guanfacine used according to item 46, wherein the transdermal therapeutic system is used to treat hypertension or attention deficit hyperactivity disorder (ADHD) in human patients and / or as a stimulant In the method of auxiliary treatment of treatment.
48. The transdermal therapeutic system comprising guanfacine according to item 46 or 47, wherein the transdermal therapeutic system is the transdermal therapeutic system according to any one of items 44 or 45.
49. Guanfacine in a method for treating human patients (preferably human patients aged from 6 to 17 years), which is administered transdermally with guanfacine by using a transdermal therapeutic system, wherein the The transdermal therapeutic system is applied to the patient's skin for at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours.
50. The guanfacine used according to item 49, wherein the guanfacine is used to treat high blood pressure or attention deficit hyperactivity disorder (ADHD) in human patients and / or as an adjunct therapy for stimulating drug therapy in.
51. Guanfacine used according to item 49 or 50, wherein the guanfacine is administered by applying a transdermal therapeutic system according to any one of items 44 or 45.
52. A method of treating human patients (preferably human patients aged from 6 to 17 years) by transdermal administration of guanfacine, wherein the transdermal therapeutic system is applied to the patient's skin for at least 24 hours, compared to It is preferably at least 72 hours, and more preferably about 84 hours.
53. A method of treating human patients by percutaneous administration of guanfacine according to item 52, wherein the method is used to treat hypertension or inattention hyperactivity disorder (ADHD) in human patients and / or as a stimulus Adjuvant treatment with medication.
54. A method of treating human patients by transdermal administration of guanfacine according to any one of items 52 or 53, wherein guanfacine is applied by applying percutaneous treatment according to any one of items 44 or 45 System.
55. A method of manufacturing a guanfacine-containing layer for use in a percutaneous treatment system according to any one of items 1 to 37 or 44 or 45, which comprises the following steps:
1) Combine at least the following components:
i) guanfacine; and
ii) at least one polysiloxane acrylic hybrid polymer;
To obtain a coating composition;
2) Apply the coating composition on the backing layer or release liner to obtain the coated coating composition; and
3) The coated coating composition is dried to form a guanfacine-containing layer.
56. The method of manufacturing a guanfacine-containing layer according to item 55, wherein the polysiloxane-based acrylic hybrid polymer is provided as a solution, and wherein the solvent is ethyl acetate or n-heptane, preferably ethyl acetate.
57. A transdermal therapeutic system obtainable by the method according to any one of items 55 or 56.
58. A transdermal therapeutic system for percutaneous administration of guanfacine, which includes a layer structure containing guanfacine, the layer structure containing guanfacine comprising:
A) Backing layer; and
B) A layer containing guanfacine, preferably a matrix layer containing guanfacine, which contains
i) Guanfacine, the amount of which is from 3 to 13% by weight based on the total weight of the layer containing guanfacine;
ii) at least one polysiloxane acrylic hybrid polymer in an amount of from 74 to 89% by weight based on the total weight of the guanfacine-containing layer;
iii) at least one dispersant, the amount of which is from 2 to 6% by weight based on the total weight of the guanfacine-containing layer;
iv) at least one penetration enhancer in an amount of from 2 to 6% by weight based on the total weight of the guanfacine-containing layer; and
v) Optionally at least one co-solvent in an amount of from 0.5 to 4% by weight based on the total weight of the guanfacine-containing layer.
59. The transdermal therapeutic system according to item 58, wherein the guanfacine-containing layer is a guanfacine-containing matrix layer, which contains
i) Guanfacine, the amount of which is from 3 to 13% by weight based on the total weight of the layer containing guanfacine;
ii) at least one polysiloxane acrylic hybrid polymer in an amount of from 74 to 89% by weight based on the total weight of the guanfacine-containing layer;
iii) Polyethylene glycol C ₈ -C ₂₀ -alkyl ethers having from 2 to 10 EO units in an amount of from 2 to 6% by weight based on the total weight of the guanfacine-containing layer;
iv) oleyl alcohol, the amount of which is from 2 to 6% by weight based on the total weight of the guanfacine-containing layer; and
v) Optionally, a graft copolymer of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol, the amount of which is from 0.5 to 4% by weight based on the total weight of the guanfacine-containing layer.
60. The percutaneous treatment system according to item 58 or 59, wherein the guanfacine-containing layer is a guanfacine-containing matrix layer, which contains
i) guanfacine, the amount of which is from 11 to 13% by weight based on the total weight of the guanfacine-containing layer;
ii) The first polysiloxyacrylic hybrid polymer whose amount is from 73 to 75% by weight based on the total weight of the guanfacine-containing layer and the second polysiloxyacrylic hybrid polymer in The total weight of the layer containing guanfacine is based on 3 to 5 wt%;
iii) Polyethylene glycol C ₈ -C ₂₀ -alkyl ether with 2 to 10 EO units, preferably polyoxyethylene (4) lauryl ether, based on the total weight of the layer containing guanfacine From 3 to 5% by weight;
iv) oleyl alcohol, the amount of which is from 3 to 5 wt% based on the total weight of the guanfacine-containing layer; and
v) Polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, the amount of which is from 0.5 to 3% by weight based on the total weight of the guanfacine-containing layer.
61. The transdermal therapeutic system according to item 60, wherein the weight ratio of polysiloxane to the acrylate phase in the first polysiloxane-based acrylic hybrid polymer is from 55:45 to 45:55, and acrylic acid is formed therein The ethylenically unsaturated monomer of the ester includes 2-ethylhexyl acrylate and methyl acrylate in a ratio from 55:45 to 45:50.
62. The percutaneous treatment system according to item 60 or 61, wherein the weight ratio of polysiloxane to the acrylate phase in the second polysiloxane-based acrylic hybrid polymer is from 55:45 to 45:55, and The acrylate-forming ethylenically unsaturated monomer contains 2-ethylhexyl acrylate and methyl acrylate in a ratio from 65:35 to 55:45.
63. The transdermal therapeutic system according to any one of items 60 to 62, wherein in the two polysiloxane-acrylic hybrid polymers, the polysiloxane phase is the internal phase and the acrylate phase is the external phase.
64. The transdermal therapeutic system according to item 58 or 59, wherein the guanfacine-containing layer is a guanfacine-containing matrix layer, which contains
i) Guanfacine, the amount of which is from 5 to 7 wt% based on the total weight of the layer containing guanfacine;
ii) The first polysiloxane-acrylic hybrid polymer, the amount of which is from 79 to 83% by weight based on the total weight of the guanfacine-containing layer, and the second polysiloxane-acrylic hybrid polymer, the amount From 3 to 5% by weight based on the total weight of the guanfacine-containing layer;
iii) Polyethylene glycol C ₈ -C ₂₀ -alkyl ether with 2 to 10 EO units, preferably polyoxyethylene (4) lauryl ether, based on the total weight of the layer containing guanfacine From 3 to 5% by weight; and
iv) Oleyl alcohol in an amount of from 3 to 5 wt% based on the total weight of the guanfacine-containing layer.
65. The transdermal therapeutic system according to item 64, wherein the weight ratio of polysiloxane to the acrylate phase in the first polysiloxane-based acrylic hybrid polymer is from 55:45 to 45:55, and acrylic acid is formed therein The ethylenically unsaturated monomer of the ester includes 2-ethylhexyl acrylate and methyl acrylate in a ratio from 55:45 to 45:50.
66. The transdermal therapeutic system according to item 64 or 65, wherein the weight ratio of polysiloxane to the acrylate phase in the second polysiloxane-based acrylic hybrid polymer is from 55:45 to 45:55, and The acrylate-forming ethylenically unsaturated monomer contains 2-ethylhexyl acrylate and methyl acrylate in a ratio from 65:35 to 55:45.
67. The percutaneous treatment system according to any one of items 64 to 66, wherein in the two polysiloxane-acrylic hybrid polymers, the polysiloxane phase is the internal phase and the acrylate phase is the external phase.
68. The percutaneous treatment system according to any one of items 58 to 67, wherein the area weight of the guanfacine-containing layer ranges from 80 to 120 g / m ² , preferably from 90 to 100 g / m ² .

Figure 1 depicts the guanfacine penetration of TTS prepared according to Examples 1a-c.

Figure 2 depicts the guanfacine penetration of TTS prepared according to Examples 2a-d.

Figure 3 depicts the guanfacine penetration of TTS prepared according to Examples 3a and 3b.

Figures 4a and 4b depict the guanfacine penetration of TTS prepared according to Examples 4a-g.

Figure 5 depicts the guanfacine penetration of TTS prepared according to Examples 5a-c and Comparative Example 1.

Figure 6 depicts the guanfacine penetration of TTS prepared according to Examples 6a-e.

Figure 7 depicts the guanfacine penetration of TTS prepared according to Examples 7a-d.

Figure 8 depicts the guanfacine penetration of TTS prepared according to Example 8a.

Figure 9 depicts the guanfacine penetration of TTS prepared according to Examples 9a-c.

Figure 10 depicts the guanfacine penetration of TTS prepared according to Comparative Examples 2a and 2b.

FIG. 11 depicts the plasma concentration of guanfacine obtained in the in vivo clinical study according to Example 10. FIG.

Claims (24)

A percutaneous treatment system for percutaneous administration of guanfacine includes a layer structure containing guanfacine, and the layer structure containing guanfacine includes: A) Backing layer; and B) The layer of guanfacine; Wherein the transdermal therapeutic system includes at least one polysiloxane acrylic hybrid polymer. According to the percutaneous treatment system of item 1 of the patent scope, The guanfafaxin-containing layer is a guanfafaxin-containing matrix layer, which includes: i) guanfacine; and ii) At least one polysiloxane acrylic hybrid polymer. According to the percutaneous treatment system of patent application scope 1 or 2, The layer structure containing guanfacine is self-adhesive, and preferably does not include an additional skin contact layer. According to the percutaneous treatment system of patent application scope 1 or 2, Wherein the guanfacine in the guanfafaxin-containing layer structure exists in the form of a free base, which is preferably dispersed in the guanfafaxin-containing layer, and / or The layer structure containing guanfacine contains guanfacine in an amount of from 1 to 100 mg / TTS, preferably from 8 to 72 mg / TTS. According to the percutaneous treatment system of patent application scope 1 or 2, Wherein the guanfafaxin-containing layer contains guanfacine, the amount of which is from 1 to 20%, more preferably from 3 to 16% by weight, based on the total weight of the guanfafaxin-containing layer. According to the percutaneous treatment system of patent application scope 1 or 2, Wherein the guanfafaxin-containing layer contains at least one polysilicoxyacrylic hybrid polymer in an amount of from 20 to 99%, preferably from 30 to 97%, based on the total weight of the guanfafacine-containing layer Best from 35 to 94% by weight; It is preferred that the at least one polysiloxane acrylic hybrid polymer includes a polysiloxane phase and an acrylate phase in a weight ratio of from 60:40 to 40:60. According to the percutaneous treatment system of the 6th scope of the patent application, The polysiloxane-based acrylic hybrid polymer is a polysiloxane-based acrylic hybrid pressure-sensitive adhesive, which contains the following reaction products: (a) Silicone-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality; (b) ethylenically unsaturated monomer; and (c) Starter. The transdermal therapeutic system according to item 7 of the patent application scope, wherein the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality contains the following condensation reaction product: (a1) polysiloxane resin , And (a2) a polysiloxane polymer, and (a3) a silicon-containing blocking agent containing acrylate or methacrylate functionality, wherein the silicon-containing blocking agent has the general formula XYR ' _b SiZ _{3- b} , where X is a monovalent group of the general formula AE, where E is -O- or -NH-, and A is acryl or methacryl, Y is a divalent having from 1 to 6 carbon atoms Alkylene, R 'is methyl or phenyl, Z is a monovalent hydrolyzable organic group or halogen, and b is 0 or 1; wherein the polysiloxane resin and polysiloxane polymer react to form a pressure sensitive Adhesive, where the silicon-containing end-capping agent is introduced before, during or after the reaction of the polysiloxane resin and the polysiloxane polymer, and in which the polysiloxane resin and the polysiloxane polymer have undergone a condensation reaction After forming the pressure-sensitive adhesive, the silicon-containing blocking agent reacts with the pressure-sensitive adhesive, or the silicon-containing blocking agent Field of the poly silicon silicone and polyethylene oxide polymer. According to the percutaneous treatment system of the 7th patent application, Wherein the ethylenically unsaturated single system is selected from the group consisting of: aliphatic acrylate, aliphatic methacrylate, cycloaliphatic acrylate, cycloaliphatic methacrylate, and combinations thereof, these compounds Each has up to 20 carbon atoms in the alkyl group, and the ethylenically unsaturated monomer is preferably a combination of 2-ethylhexyl acrylate and methyl acrylate, particularly preferably from 40:60 to 70:30 ratio. According to the percutaneous treatment system of the 7th patent application, Among the following reaction products: (a) Silicone-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality; (b) ethylenically unsaturated monomer; and (c) Starter Contains a continuous acrylic external phase and a discontinuous polysiloxane internal phase. According to the percutaneous treatment system of patent application scope 1 or 2, Wherein the guanfacine-containing layer further comprises at least one additive selected from the group consisting of: a dispersant, a penetration enhancer, and a co-solvent. The transdermal therapeutic system according to item 11 of the patent application scope, wherein the dispersant is selected from the group consisting of: esters of fatty acids and polyols, fatty alcohols, polyethylene glycol having a number average molecular weight of 300 to 400, Polyethylene glycol alkyl ether, and wherein the dispersant is preferably a polyethylene glycol C ₈ -C ₂₀ -alkyl ether having 2 to 10 EO units. The transdermal therapeutic system according to item 11 of the patent application scope, wherein the penetration enhancer is selected from the group consisting of diethylene glycol monoethyl ether (transcutol), oleic acid, levulinic acid, glycerin Caprylic / capric triglyceride, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, triacetin, dimethyl Propyl urea and oleyl alcohol, and preferably oleyl alcohol. The percutaneous treatment system according to item 11 of the patent application scope, wherein the cosolvent is selected from the group consisting of: copolymers derived from esters of acrylic acid and methacrylic acid, polyvinylpyrrolidone, vinylpyrrolidine Ketone-vinyl acetate copolymer, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and preferably polyvinyl caprolactam-polyvinyl acetate-polyethylene Glycol graft copolymer. The percutaneous treatment system according to claim 1 or 2, wherein the area weight of the guanfacine-containing layer ranges from 40 to 250 g / m ² , preferably from 50 to 180 g / m ² ; and / or The release area ranges from 1 to 100 cm ² , preferably from 2.5 to 50 cm ² . According to the percutaneous treatment system of patent application scope 1 or 2, Wherein the transdermal therapeutic system is delivered transdermally in a steady state to provide plasma concentrations of guanfacine from 1 to 20 ng / ml, preferably from 1 to 15 ng / ml. The percutaneous treatment system according to item 1 or 2 of the patent application scope, which has: AUC _0-24h of about 10 to 600 ng * h / ml, preferably about 20 to 400 ng * h / ml; and / or AUC _{0 -72h} is about 30 to 1800 ng * h / ml, preferably about 60 to 1200 ng * h / ml; and / or AUC _0-84h is about 35 to 2100 ng * h / ml, preferably about 70 to 1400 ng * h / ml; and / or the ratio of C _max to C ₈₄ less than 3.5; and / or the ratio of C _max to C ₇₂ less than 3.0; and / or the ratio of C _max to C ₂₄ less than 2.0. The percutaneous treatment system according to item 1 or 2 of the patent application scope is used in a method for treating human patients (preferably human patients from 6 to 17 years old). The percutaneous treatment system according to item 1 or 2 of the patent application scope, which is used to treat high blood pressure or attention deficit hyperactivity disorder (ADHD) of human patients (preferably human patients from 6 to 17 years old) and / Or used as an adjunct therapy for stimulating drug therapy. The percutaneous treatment system according to claim 1 or 2, wherein the percutaneous treatment system is applied to the patient's skin for at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours. A transdermal therapeutic system for transdermal administration of guanfacine, which includes a layer structure containing guanfacine, wherein the transdermal therapeutic system provides one or more percutaneous delivery systems selected from the group consisting of pharmacokinetic parameters: range from 10 to 600 (ng / mL) h of AUC _0-24, of from 30 to 1800 (ng / mL) AUC h of _0-72, from 35 to 2100 (ng / mL) h of AUC _{0 -84} , the ratio of C _max to C ₂₄ less than 2.0, the ratio of C _max to C ₇₂ less than 3.0, and the ratio of C _max to C ₈₄ less than 3.5. A transdermal therapeutic system comprising guanfacine, which is a method for transdermal administration of guanfacine to treat human patients (preferably human patients aged from 6 to 17 years), wherein the transdermal therapeutic system is The application to the skin of the patient takes at least 24 hours, preferably at least 72 hours, more preferably about 84 hours. The percutaneous treatment system containing guanfacine according to item 22 of the patent application scope, wherein the percutaneous treatment system is used to treat high blood pressure or attention deficit hyperactivity disorder (ADHD) in human patients and / or as a stimulant In the method of auxiliary treatment of treatment. The percutaneous treatment system according to claim 22 or 23, wherein the percutaneous treatment system is the percutaneous treatment system according to claim 21.